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15 September 2024, Volume 19 Issue 9 Previous Issue   

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Does MgSO4 protect the preterm brain? Dissecting its role in the pathophysiology of hypoxic ischemic encephalopathy Robert Galinsky, Laura Bennet, Alistair J. Gunn 2024, 19 (9):  1861-1862.  doi: 10.4103/1673-5374.390977 Abstract ( 80 )   PDF (660KB) ( 40 )   Save Mitigating preterm encephalopathy continues to be one of the greatest challenges in perinatal medicine. Preterm encephalopathy is associated with high mortality, serious morbidity, and significant socio-economic impacts on the individuals, their families, and public health sectors and welfare systems that last a lifetime. The cost of disability associated with preterm brain injury continues to rise. Prevention of this injury, and disability, would significantly reduce this socioeconomic burden.  Related Articles | Metrics

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Breaking the brain barrier: cell competition in neural development and disease Patrizia Morciano, Daniela Grifoni 2024, 19 (9):  1863-1864.  doi: 10.4103/1673-5374.391185 Abstract ( 62 )   PDF (2407KB) ( 71 )   Save General information on cell competition: Social behaviors are the basis of biological life. Like species and populations, cell communities experience Darwinian ecological interactions, and in case space and nutrient availability are not uniform throughout the tissue, they begin to compete for ground occupancy. In the 1970s, studies carried out by Drosophila geneticists pioneered the concept of cell competition, observing that genetic heterogeneity in a developing tissue led to the elimination of suboptimal cells (called losers) and the concurrent expansion of the fittest (accordingly named winners). This mechanism fits the logic underlying organ development, where tissue heterogeneity due to the intermingling of cells from different compartments may disrupt the entire process. Decades after, cell competition was associated with different MYC levels in confronting cells: high-MYC-expressing cells repeatedly eliminated low-MYC-expressing neighbors and grew up to colonize the whole territory (Gallant, 2005). Subsequent studies led to the identification of MYC-mediated cell competition (MMCC) as a central process in embryonic development, from flies to mammals (Penzo-Mendez and Stanger, 2014). Over time, different molecules and pathways have been associated with cell competition, and now this mechanism is known to be active in different tissues and organs, engaging different cell histotypes, from flies to humans. Losers forfeit by death, cannibalism, displacement, differentiation or quiescence, and winners achieve by proliferation, survival, hypertrophy or stemness maintenance (Baker, 2020). Independent of where, when, and how it occurs, cell competition pursues the stereotyped functional principle of selecting and expanding the most appropriate cells in each specific condition. In this perspective, we discuss the most relevant findings on the role of cell competition in neural cells.  Related Articles | Metrics

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Nrf2 as a potential target for the treatment of epilepsy Prince Kumar Singh, Tawfeeq Shekh-Ahmad 2024, 19 (9):  1865-1866.  doi: 10.4103/1673-5374.390975 Abstract ( 134 )   PDF (5127KB) ( 62 )   Save Epilepsy is a prevalent chronic brain disorder that is characterized by a persistent predisposition to recurrently generate epileptic seizures and is often associated with cognitive and psychological consequences. Epilepsy affects approximately 65 million individuals, including both males and females of all ages worldwide, and poses a significant burden on patients, their families, and the health system (Vezzani et al., 2019). Although a substantial number of anti-seizure medications have been approved by the FDA for the treatment of epilepsy, these therapies fail to prevent the development of seizures or permanently halt the occurrence of chronic disease (Glauser et al., 2013), and more than 30% of patients with epilepsy remain resistant to these medications and endure recurrent spontaneous seizures.  Therefore, the search for alternative therapeutic targets with anti-epileptogenic and anti-seizure potential could offer a promising avenue for addressing the challenges related to drug-resistant epilepsy treatment. Drug resistance is a particular challenge in patients with temporal lobe epilepsy, in which seizures originate mostly in the hippocampus, and many of these cases are acquired and arise following brain insults, such as prolonged seizures, traumatic brain injuries, or strokes. Several studies have confirmed that oxidative stress (OS) and elevated levels of reactive oxygen species (ROS) play crucial roles in the development and progression of epilepsy following such brain injuries. Related Articles | Metrics

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New complex physiological findings evolve hypothesized mechanisms of Dravet syndrome MacKenzie A. Howard 2024, 19 (9):  1867-1868.  doi: 10.4103/1673-5374.390967 Abstract ( 64 )   PDF (766KB) ( 20 )   Save Developmental and epileptic encephalopathies (DEEs) are neurological disorders generally involving medically intractable seizures and a diverse array of comorbid neuropsychiatric delays and deficits that may severely affect cognition, mood, sleep, social behavior, movement control, learning, and/or memory. Dravet syndrome (DS), also known as Severe Myoclonic Epilepsy of Infancy, is a rare disease but one of the more common DEEs, afflicting children in infancy and causing severe lifelong struggles and high risk of early mortality (Villas et al., 2017). Most people with DS have a deleterious variant to one copy of the SCN1A gene, which encodes the voltage-gated sodium channel Nav1.1. Variants of SCN1B, HCN1, and other genes have also been identified as potentially causative in diagnosed cases of DS. Animal models across phyla with changes to the expression of Scn1a or its ortholog present with seizures, neurological deficits, and early mortality analogous to DS. Early animal model work provided a wealth of knowledge about the role of Nav1.1 in neural excitability and dysfunction and brought about the hypothesis that GABAergic interneuron hypoexcitability was the underlying cause of DS. Here we provide a brief review of some recent studies that broaden the interneuron hypothesis, revealing cell phenotypes and circuit interactions that are subtle, complex, and at times counterintuitive, all while deepening our understanding of the intricate nature of neural processing and the mechanisms of neurological disease. Related Articles | Metrics

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Autolysosomal acidification impairment as a mediator for TNFR1 induced neuronal necroptosis in Alzheimer’s disease Evridiki Asimakidou, Richard Reynolds, Anna M. Barron, Chih Hung Lo 2024, 19 (9):  1869-1870.  doi: 10.4103/1673-5374.390979 Abstract ( 91 )   PDF (10023KB) ( 26 )   Save Neuronal necroptosis–an emerging form of regulated cell death associated with neuroinflammatory signaling: Alzheimer’s disease (AD) is characterized by the presence of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles as well as progressive neuronal loss. Recent evidence has suggested that prolonged neuroinflammation with increased levels of cytokines, arising from neuronal injury, innate immune responses from glial cells, and peripheral inflammation, leads to neuronal death and AD progression. Neuronal necroptosis is an emerging form of regulated cell death associated with neuroinflammatory signaling. Necroptosis typically occurs in response to sustained inflammation while apoptosis facilitates normal turnover of cellular contents important for growth and development. By combining features of apoptosis and necrosis, necroptosis has been proposed to constitute a more comprehensive mechanistic explanation for neurodegeneration, which is less likely to occur by the immunologically silent apoptotic cell death or by the acute occurrence of necrosis after cellular stress (Jayaraman and Reynolds, 2022). Related Articles | Metrics

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Highly toxic Aβ begets more Aβ Merc M. Kemeh, Noel D. Lazo 2024, 19 (9):  1871-1872.  doi: 10.4103/1673-5374.390983 Abstract ( 104 )   PDF (407KB) ( 27 )   Save Alzheimer’s disease (AD) is the most common form of dementia-the 7th leading cause of death worldwide. At the tissue level, AD is characterized by the presence of extracellular amyloid plaques that are comprised primarily of the amyloid-β peptide (Aβ), and by intraneuronal neurofibrillary tangles composed of tau. Molecular genetics of early-onset AD and longitudinal brain-imaging studies of late-onset AD indicate that extracellular Aβ deposition, in general, precedes neurofibrillary tangle formation in neurons (Hampel et al., 2021; Young-Pearse et al., 2023). Related Articles | Metrics

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Traumatic brain injury treatment using a rodent model of homelessness Molly Monsour, Cesar V. Borlongan 2024, 19 (9):  1873-1874.  doi: 10.4103/1673-5374.391186 Abstract ( 63 )   PDF (417KB) ( 22 )   Save Introduction: Traumatic brain injury (TBI) is a common diagnosis among veterans secondary to combat experiences. TBI is also rampant among those experiencing homelessness, possibly due to veterans making up 12.3% of the homeless population (Tsai and Rosenheck, 2015), or due to the high risk of violence or trauma among those experiencing homelessness. TBI is up to 10× more prevalent among those experiencing homelessness (Stubbs et al., 2020; Dell et al., 2021). In a study involving 1215 patients, 58% of patients discharged from trauma centers without stable housing were diagnosed with TBI compared to 48% of those discharged to a home (Dell et al., 2021). In a meta-analysis of 9702 homeless or unstably housed individuals, the lifetime prevalence of TBI was 53.1% (Stubbs et al., 2020). TBI has known underlying neuroinflammatory changes, and the chronic stressors of homelessness may further contribute to systemic inflammation (Brisson et al., 2020). Our research team questioned whether the additional stress associated with homelessness may exacerbate the functional deficits and pathophysiological changes in TBI. Related Articles | Metrics

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PML nuclear bodies: new players in familial amyotrophic lateral sclerosis-frontotemporal dementia? Anand Goswami, Serena Carra 2024, 19 (9):  1875-1876.  doi: 10.4103/1673-5374.391183 Abstract ( 97 )   PDF (602KB) ( 16 )   Save Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two closely related disorders with overlapping clinical, genetic, and neuropathological features, forming a continuous disease spectrum (Ling et al., 2013). The major pathological hallmark of ALS and FTD are the depletion from the nucleus of the RNA-binding proteins TAR DNA‐binding protein 43 (TDP-43) and FUsed in Sarcoma (FUS) and their abnormal accumulation in ubiquitin-positive cytoplasmic inclusions (Ling et al., 2013). TDP-43 and FUS, whose genetic mutations are associated with the familial forms of ALS-FTD, participate in the regulation of RNA maturation and DNA repair, key processes whose dysregulation is central in ALS-FTD pathogenesis, along with the impairment of protein homeostasis (proteostasis) (Ling et al., 2013). Related Articles | Metrics

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Recent advances and future therapy development for Alzheimer’s disease and related disorders Megan Hong, Gal Bitan 2024, 19 (9):  1877-1878.  doi: 10.4103/1673-5374.391182 Abstract ( 115 )   PDF (734KB) ( 42 )   Save Over 55 million people globally live with Alzheimer’s disease (AD) or related dementias (ADRD) and the number is expected to double every twenty years. Until recently, only symptomatic treatments were available to patients with AD, including acetylcholine esterase inhibitors, of which the last one, galantamine, was approved by the US Food and Drug Administration (FDA) in 2001, and the noncompetitive N-methyl-D-aspartate receptor antagonist, memantine, approved in 2003. Thus, for nearly 20 years, despite numerous clinical trials, the landscape for developing new therapy looked barren and grim (Cummings et al., 2022). Then, in June 2021, FDA granted accelerated approval to aducanumab (AduhelmTM), an anti-amyloid-β (Aβ) monoclonal antibody (mAb) targeting “protofibrils”, which were described in the 1990s (Walsh et al., 1997) and shown later to be key neurotoxins. Aducanumab became the first approved drug addressing the underlying pathology of AD, albeit with substantial adverse effects. Due to the side effects and relatively weak efficacy data, the FDA approval was highly controversial (Kuller and Lopez, 2021): Ten of the eleven members of the scientific advisory committee voted against approval and the eleventh voted uncertain. Following the FDA’s decision, three committee members quit in protest. Related Articles | Metrics

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Non-linear dynamic state-space network modeling for decoding neurodegeneration Venkata C. Chirumamilla, Chi Wang Ip, Martin Reich, Robert Peach, Jens Volkmann, Bahman Nasseroleslami, Muthuraman Muthuraman 2024, 19 (9):  1879-1880.  doi: 10.4103/1673-5374.391187 Abstract ( 88 )   PDF (409KB) ( 39 )   Save Neurodegenerative disorders represent a pervasive global health challenge, yet therapeutic options remain conspicuously limited. These disorders are inherently dynamic processes within the central nervous system, unfolding across distinct sub-stages: initial structural neuronal alterations (sub-stage 1), functional impairment (sub-stage 2), and culminating in neuronal death (sub-stage 3). Previous studies have revealed shared pathological features between amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) (van Rheenen et al., 2021; Mantle and Hargreaves, 2022) including common genetic risk factors identified through genome-wide association studies (van Rheenen et al., 2021). Both disorders manifest similar neurodegenerative mechanisms, such as oligomer formation, aberrant protein accumulation, and protein misfolding-specifically, superoxide dismutase 1 in ALS and α-synuclein in PD. Mitochondrial dysfunction further serves as a common denominator in the pathogenesis of ALS and PD (Mantle and Hargreaves, 2022).  Related Articles | Metrics

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Primary lateral sclerosis: more than just an upper motor neuron disease Ee Ling Tan, Jasmin Lope, Peter Bede 2024, 19 (9):  1881-1882.  doi: 10.4103/1673-5374.391184 Abstract ( 116 )   PDF (1115KB) ( 39 )   Save Advances in clinical care and recent research achievements: Primary lateral sclerosis (PLS) has traditionally been regarded as a pure upper motor neuron condition, a view perpetuated by most medical textbooks. Recent research has challenged the classical view that only the motor cortex and the descending corticospinal tracts are affected in PLS and the clinical and radiological profile of the condition has now been characterized by more nuanced descriptions. Research in PLS has gained unprecedented momentum in recent years, resulting in the painstaking characterization of disease burden patterns both post mortem and in vivo. Post mortem studies have confirmed distinguishing characteristics between amyotrophic lateral sclerosis (ALS) and PLS cohorts, namely the scarcity of TAR DNA-binding protein 43 pathology in the spinal anterior horns (Mackenzie and Briemberg, 2020). Genetic studies of larger cohorts have helped to delineate PLS from ALS and hereditary spastic paraplegia. While the core imaging signature of PLS is associated with primary motor cortex, corpus callosum and pyramidal tract degeneration (Finegan et al., 2019a), recent imaging studies have demonstrated frontotemporal changes, brainstem-cortex disconnection (Tahedl et al., 2023b), cerebellar involvement (Finegan et al., 2022) and subcortical grey matter degeneration (Finegan et al., 2019b). The pathognomonic clinical features of PLS such as spasticity, bulbar impairment, and pseudobulbar affect (Tahedl et al., 2023a) have been complemented by reports of language deficits, memory impairment, and executive dysfunction (de Vries et al., 2019). Two important practical developments have also taken place. The new consensus diagnostic criteria published in 2020 reduced the minimum symptom duration criterion to diagnose patients with PLS and introduced the categories of “definite” and “probable” PLS. The validity of the new criteria has already been demonstrated by cohorts of “probable” PLS patients harboring clinical and imaging features consistent with PLS and transitioning to “definite” PLS over time (Finegan et al., 2020). Up to recently, the revised ALS functional rating scale was widely administered to cohorts of PLS patients as a composite measure of motor disability. The recent development of the PLS functional rating scale is an important new tool to accurately appraise and monitor PLS-associated disability. Developed by Mitsumoto et al. and published in 2020, this new instrument has excellent intra-rater, inter-rater, and test-retest reliability and is increasingly utilized worldwide. The introduction of the new diagnostic criteria and the development of the PLS-specific functional rating scale have important practical ramifications for an earlier diagnosis and more accurate clinical monitoring. While no disease-modifying treatment has been developed, considerable advances have taken place in the management of common, PLS-associated symptoms such as pseudobulbar affect. The departure from isolated, single-center research efforts, to consortium-lead collaborative initiatives is likely to give PLS research further momentum. Recent research has also contributed to the development of precision clinical, biofluid, and radiological markers, which are indispensable for successful pharmacological trials.  Related Articles | Metrics

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FE65: a hub for neurodevelopment Yuqi Zhai, Laura Lok-Haang Ng, Dennis Dik-Long Chau, Kwok-Fai Lau 2024, 19 (9):  1883-1884.  doi: 10.4103/1673-5374.391188 Abstract ( 81 )   PDF (540KB) ( 19 )   Save FE65, initially identified as a binding partner of amyloid precursor protein (APP), is an adaptor protein enriched in the brain and regulated during development. FE65 belongs to the FE65 protein family. This family is comprised of three members, FE65, FE65 like-1 (FE65L1), and FE65 like-2 (FE65L2). The three members share a conserved structure: a tryptophan-tryptophan (WW) domain and two successive phosphotyrosine-binding (PTB) domains. Despite being structurally similar, the three proteins differ in their expression patterns. FE65 is brain-enriched while FE65L1 and FE65L2 are more ubiquitously expressed. Therefore, FE65 has drawn more research interest than the other two homologs. Insights into the potential functions of the FE65 family have been obtained through studies on its interaction partners. Recently, emerging evidence suggests multiple roles of FE65 and its interactors during neuronal developmental processes including neurogenesis, neuronal migration and positioning, neurite outgrowth, and synaptic plasticity (Figure 1). Related Articles | Metrics

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A divergent pattern in functional connectivity: a transdiagnostic perspective Lu Zhang, Lorenzo Pini 2024, 19 (9):  1885-1886.  doi: 10.4103/1673-5374.390982 Abstract ( 65 )   PDF (563KB) ( 31 )   Save Functional magnetic resonance imaging (fMRI) is a popular tool used to investigate not only how the brain responds to specific stimuli during sensorimotor or cognitive tasks, but also brain activity at rest. The physics beyond this approach is based on the analysis of the blood oxygenation level-dependent signal. When performing a task, regions activated by a specific goal exhibit changes in the blood oxygenation level-dependent signal compared to the resting phase. Looking at the difference between the task-evoked signal and the spontaneous fluctuations allows identifying which brain regions are activated by specific tasks. However, spontaneous fluctuations are no more considered as a mere epiphenomenon as they allow unravelling how the brain “works” during resting state conditions. This approach is referred to as resting-state fMRI (rs-fMRI). Starting from this signal it is possible to quantify the functional connectivity (FC), a metric used to identify which brain regions show signal synchronization, and therefore are considered functionally connected within specific resting-state networks. Each resting-state network is characterized by specific spatiotemporal patterns, linked with sensory and high-cognitive order functions (e.g., memory, attention, and language), as highlighted by a study by Yeo et al. (2011). Being vascular in nature, rs-fMRI represents an indirect measure of neural connectivity. Despite this limitation, the study of rs-fMRI signals deeply increased our knowledge about brain mechanisms underlying cognitive and sensory abilities. Related Articles | Metrics

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Astrocyte chloride, excitatory-inhibitory balance and epilepsy Verena Untiet, Maiken Nedergaard, Alexei Verkhratsky 2024, 19 (9):  1887.  doi: 10.4103/1673-5374.390981 Abstract ( 109 )   PDF (778KB) ( 53 )   Save Excitation and inhibition are at the core of brain function and malfunction. To sustain the activity of neuronal networks over time and space, glutamatergic excitation is balanced by GABAergic inhibition. The equipoise of excitation and inhibition, known as the excitation/inhibition (E/I) balance, is crucial for proper brain function. The E/I balance is highly dynamic and shifts across different brain states: wakefulness primarily augments excitatory activity, while sleep promotes a decrease in excitation and an increase in inhibition (Bridi et al., 2020). Neuronal activity during various brain states is primarily regulated by neurotransmitters (Schiemann et al., 2015), alongside non-synaptic mechanisms that operate on a slower timescale. The non-synaptic mechanisms are many, with the ionic composition of the extracellular space playing a significant role; altering extracellular ion concentrations affects sleep, arousal, electroencephalogram patterns, and behavioral states (Ding et al., 2016). Related Articles | Metrics

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Statistical evaluation of cluster formation of relapse in neuromyelitis optica spectrum disorder Tetsuya Akaishi, Ichiro Nakashima 2024, 19 (9):  1888-1889.  doi: 10.4103/1673-5374.390980 Abstract ( 61 )   PDF (1233KB) ( 15 )   Save Evaluating the cluster formation of clinical attacks in chronic relapsing diseases is an important statistical issue because the presence of attack clusters may influence therapeutic strategies for relapse prevention. We recently reported the occurrence of unevenly clustered attacks in patients with anti-aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD) (Akaishi et al., 2020a). The presence of attack clusters implies the necessity of implementing intensive relapse prevention with highly efficient drugs, such as the anti-complement C5 monoclonal antibody (eculizumab), during the cluster period (Pittock et al., 2019). This is especially true in diseases in which relapse is an established factor that causes severe and irreversible sequelae, such as NMOSD (Akaishi et al., 2020b). In this report, we present the following two statistical methods for evaluating the presence of uneven cluster formation of attacks in relapsing diseases including anti-AQP4-positive NMOSD: (1) the chi-square goodness-of-fit test and (2) the Kolmogorov-Smirnov (KS) test. Related Articles | Metrics

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Microglial NLRP3 inflammasome-mediated neuroinflammation and therapeutic strategies in depression Qiuqin Han, Wenhui Li, Peiqing Chen, Lijuan Wang, Xiwen Bao, Renyan Huang, Guobin Liu, Xiaorong Chen 2024, 19 (9):  1890-1898.  doi: 10.4103/1673-5374.390964 Abstract ( 536 )   PDF (1537KB) ( 145 )   Save Previous studies have demonstrated a bidirectional relationship between inflammation and depression. Activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and NLR family pyrin domain-containing 3 (NLRP3) inflammasomes is closely related to the pathogenesis of various neurological diseases. In patients with major depressive disorder, NLRP3 inflammasome levels are significantly elevated. Understanding the role that NLRP3 inflammasome-mediated neuroinflammation plays in the pathogenesis of depression may be beneficial for future therapeutic strategies. In this review, we aimed to elucidate the mechanisms that lead to the activation of the NLRP3 inflammasome in depression as well as to provide insight into therapeutic strategies that target the NLRP3 inflammasome. Moreover, we outlined various therapeutic strategies that target the NLRP3 inflammasome, including NLRP3 inflammatory pathway inhibitors, natural compounds, and other therapeutic compounds that have been shown to be effective in treating depression. Additionally, we summarized the application of NLRP3 inflammasome inhibitors in clinical trials related to depression. Currently, there is a scarcity of clinical trials dedicated to investigating the applications of NLRP3 inflammasome inhibitors in depression treatment. The modulation of NLRP3 inflammasomes in microglia holds promise for the management of depression. Further investigations are necessary to ascertain the efficacy and safety of these therapeutic approaches as potential novel antidepressant treatments. Related Articles | Metrics

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How do neurons age? A focused review on the aging of the microtubular cytoskeleton Brad Richardson, Thomas Goedert, Shmma Quraishe, Katrin Deinhardt, Amritpal Mudher 2024, 19 (9):  1899-1907.  doi: 10.4103/1673-5374.390974 Abstract ( 152 )   PDF (1064KB) ( 78 )   Save Aging is the leading risk factor for Alzheimer’s disease and other neurodegenerative diseases. We now understand that a breakdown in the neuronal cytoskeleton, mainly underpinned by protein modifications leading to the destabilization of microtubules, is central to the pathogenesis of Alzheimer’s disease. This is accompanied by morphological defects across the somatodendritic compartment, axon, and synapse. However, knowledge of what occurs to the microtubule cytoskeleton and morphology of the neuron during physiological aging is comparatively poor. Several recent studies have suggested that there is an age-related increase in the phosphorylation of the key microtubule stabilizing protein tau, a modification, which is known to destabilize the cytoskeleton in Alzheimer’s disease. This indicates that the cytoskeleton and potentially other neuronal structures reliant on the cytoskeleton become functionally compromised during normal physiological aging. The current literature shows age-related reductions in synaptic spine density and shifts in synaptic spine conformation which might explain age-related synaptic functional deficits. However, knowledge of what occurs to the microtubular and actin cytoskeleton, with increasing age is extremely limited. When considering the somatodendritic compartment, a regression in dendrites and loss of dendritic length and volume is reported whilst a reduction in soma volume/size is often seen. However, research into cytoskeletal change is limited to a handful of studies demonstrating reductions in and mislocalizations of microtubule-associated proteins with just one study directly exploring the integrity of the microtubules. In the axon, an increase in axonal diameter and age-related appearance of swellings is reported but like the dendrites, just one study investigates the microtubules directly with others reporting loss or mislocalization of microtubule-associated proteins. Though these are the general trends reported, there are clear disparities between model organisms and brain regions that are worthy of further investigation. Additionally, longitudinal studies of neuronal/cytoskeletal aging should also investigate whether these age-related changes contribute not just to vulnerability to disease but also to the decline in nervous system function and behavioral output that all organisms experience. This will highlight the utility, if any, of cytoskeletal fortification for the promotion of healthy neuronal aging and potential protection against age-related neurodegenerative disease. This review seeks to summarize what is currently known about the physiological aging of the neuron and microtubular cytoskeleton in the hope of uncovering mechanisms underpinning age-related risk to disease. Related Articles | Metrics

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Brain dysfunctions and neurotoxicity induced by psychostimulants in experimental models and humans: an overview of recent findings Marcello Serra, Nicola Simola, Alexia E. Pollack, Giulia Costa 2024, 19 (9):  1908-1918.  doi: 10.4103/1673-5374.390971 Abstract ( 88 )   PDF (1266KB) ( 71 )   Save Preclinical and clinical studies indicate that psychostimulants, in addition to having abuse potential, may elicit brain dysfunctions and/or neurotoxic effects. Central toxicity induced by psychostimulants may pose serious health risks since the recreational use of these substances is on the rise among young people and adults. The present review provides an overview of recent research, conducted between 2018 and 2023, focusing on brain dysfunctions and neurotoxic effects elicited in experimental models and humans by amphetamine, cocaine, methamphetamine, 3,4-methylenedioxymethamphetamine, methylphenidate, caffeine, and nicotine. Detailed elucidation of factors and mechanisms that underlie psychostimulant-induced brain dysfunction and neurotoxicity is crucial for understanding the acute and enduring noxious brain effects that may occur in individuals who use psychostimulants for recreational and/or therapeutic purposes. Related Articles | Metrics

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Hypothalamic circuits and aging: keeping the circadian clock updated Rosa Vázquez-Lizarraga, Lucia Mendoza-Viveros, Carolina Cid-Castro, Sareni Ruiz-Montoya, Erick Carreño-Vázquez, Ricardo Orozco-Solis 2024, 19 (9):  1919-1928.  doi: 10.4103/1673-5374.389624 Abstract ( 100 )   PDF (914KB) ( 120 )   Save Over the past century, age-related diseases, such as cancer, type-2 diabetes, obesity, and mental illness, have shown a significant increase, negatively impacting overall quality of life. Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels, including transcriptional, translational, and post-translational processes, resulting from cellular stress and circadian derangements. The circadian clock emerges as a key regulator, sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes, such as stem-cell function, cellular stress responses, and inter-tissue communication, which become disrupted during aging. Given the crucial role of hypothalamic circuits in regulating organismal physiology, metabolic control, sleep homeostasis, and circadian rhythms, and their dependence on these processes, strategies aimed at enhancing hypothalamic and circadian function, including pharmacological and non-pharmacological approaches, offer systemic benefits for healthy aging. Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions, like the hypothalamus, while reducing side effects associated with systemic drug delivery, thereby presenting new therapeutic possibilities for diverse age-related conditions. Related Articles | Metrics

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Post-transcriptional mechanisms controlling neurogenesis and direct neuronal reprogramming Elsa Papadimitriou, Dimitra Thomaidou 2024, 19 (9):  1929-1939.  doi: 10.4103/1673-5374.390976 Abstract ( 80 )   PDF (2740KB) ( 57 )   Save Neurogenesis is a tightly regulated process in time and space both in the developing embryo and in adult neurogenic niches. A drastic change in the transcriptome and proteome of radial glial cells or neural stem cells towards the neuronal state is achieved due to sophisticated mechanisms of epigenetic, transcriptional, and post-transcriptional regulation. Understanding these neurogenic mechanisms is of major importance, not only for shedding light on very complex and crucial developmental processes, but also for the identification of putative reprogramming factors, that harbor hierarchically central regulatory roles in the course of neurogenesis and bare thus the capacity to drive direct reprogramming towards the neuronal fate. The major transcriptional programs that orchestrate the neurogenic process have been the focus of research for many years and key neurogenic transcription factors, as well as repressor complexes, have been identified and employed in direct reprogramming protocols to convert non-neuronal cells, into functional neurons. The post-transcriptional regulation of gene expression during nervous system development has emerged as another important and intricate regulatory layer, strongly contributing to the complexity of the mechanisms controlling neurogenesis and neuronal function. In particular, recent advances are highlighting the importance of specific RNA binding proteins that control major steps of mRNA life cycle during neurogenesis, such as alternative splicing, polyadenylation, stability, and translation. Apart from the RNA binding proteins, microRNAs, a class of small non-coding RNAs that block the translation of their target mRNAs, have also been shown to play crucial roles in all the stages of the neurogenic process, from neural stem/progenitor cell proliferation, neuronal differentiation and migration, to functional maturation. Here, we provide an overview of the most prominent post-transcriptional mechanisms mediated by RNA binding proteins and microRNAs during the neurogenic process, giving particular emphasis on the interplay of specific RNA binding proteins with neurogenic microRNAs. Taking under consideration that the molecular mechanisms of neurogenesis exert high similarity to the ones driving direct neuronal reprogramming, we also discuss the current advances in in vitro and in vivo direct neuronal reprogramming approaches that have employed microRNAs or RNA binding proteins as reprogramming factors, highlighting the so far known mechanisms of their reprogramming action. Related Articles | Metrics

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Application of artificial hibernation technology in acute brain injury Xiaoni Wang, Shulian Chen, Xiaoyu Wang, Zhen Song, Ziqi Wang, Xiaofei Niu, Xiaochu Chen, Xuyi Chen 2024, 19 (9):  1940-1946.  doi: 10.4103/1673-5374.390968 Abstract ( 161 )   PDF (6047KB) ( 63 )   Save Controlling intracranial pressure, nerve cell regeneration, and microenvironment regulation are the key issues in reducing mortality and disability in acute brain injury. There is currently a lack of effective treatment methods. Hibernation has the characteristics of low temperature, low metabolism, and hibernation rhythm, as well as protective effects on the nervous, cardiovascular, and motor systems. Artificial hibernation technology is a new technology that can effectively treat acute brain injury by altering the body’s metabolism, lowering the body’s core temperature, and allowing the body to enter a state similar to hibernation. This review introduces artificial hibernation technology, including mild hypothermia treatment technology, central nervous system regulation technology, and artificial hibernation-inducer technology. Upon summarizing the relevant research on artificial hibernation technology in acute brain injury, the research results show that artificial hibernation technology has neuroprotective, anti-inflammatory, and oxidative stress-resistance effects, indicating that it has therapeutic significance in acute brain injury. Furthermore, artificial hibernation technology can alleviate the damage of ischemic stroke, traumatic brain injury, cerebral hemorrhage, cerebral infarction, and other diseases, providing new strategies for treating acute brain injury. However, artificial hibernation technology is currently in its infancy and has some complications, such as electrolyte imbalance and coagulation disorders, which limit its use. Further research is needed for its clinical application. Related Articles | Metrics

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The functions of exosomes targeting astrocytes and astrocyte-derived exosomes targeting other cell types Hongye Xu, He Li, Ping Zhang, Yuan Gao, Hongyu Ma, Tianxiang Gao, Hanchen Liu, Weilong Hua, Lei Zhang, Xiaoxi Zhang, Pengfei Yang, Jianmin Liu 2024, 19 (9):  1947-1953.  doi: 10.4103/1673-5374.390961 Abstract ( 144 )   PDF (27416KB) ( 48 )   Save Astrocytes are the most abundant glial cells in the central nervous system; they participate in crucial biological processes, maintain brain structure, and regulate nervous system function. Exosomes are cell-derived extracellular vesicles containing various bioactive molecules including proteins, peptides, nucleotides, and lipids secreted from their cellular sources. Increasing evidence shows that exosomes participate in a communication network in the nervous system, in which astrocyte-derived exosomes play important roles. In this review, we have summarized the effects of exosomes targeting astrocytes and the astrocyte-derived exosomes targeting other cell types in the central nervous system. We also discuss the potential research directions of the exosome-based communication network in the nervous system. The exosome-based intercellular communication focused on astrocytes is of great significance to the biological and/or pathological processes in different conditions in the brain. New strategies may be developed for the diagnosis and treatment of neurological disorders by focusing on astrocytes as the central cells and utilizing exosomes as communication mediators. Related Articles | Metrics

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Rebuilding insight into the pathophysiology of Alzheimer’s disease through new blood-brain barrier models Kinya Matsuo, Hideaki Nshihara 2024, 19 (9):  1954-1960.  doi: 10.4103/1673-5374.390978 Abstract ( 101 )   PDF (858KB) ( 94 )   Save The blood-brain barrier is a unique function of the microvasculature in the brain parenchyma that maintains homeostasis in the central nervous system. Blood-brain barrier breakdown is a common pathology in various neurological diseases, such as Alzheimer’s disease, stroke, multiple sclerosis, and Parkinson’s disease. Traditionally, it has been considered a consequence of neuroinflammation or neurodegeneration, but recent advanced imaging techniques and detailed studies in animal models show that blood-brain barrier breakdown occurs early in the disease process and may precede neuronal loss. Thus, the blood-brain barrier is attractive as a potential therapeutic target for neurological diseases that lack effective therapeutics. To elucidate the molecular mechanism underlying blood-brain barrier breakdown and translate them into therapeutic strategies for neurological diseases, there is a growing demand for experimental models of human origin that allow for functional assessments. Recently, several human induced pluripotent stem cell-derived blood-brain barrier models have been established and various in vitro blood-brain barrier models using microdevices have been proposed. Especially in the Alzheimer’s disease field, the human evidence for blood-brain barrier dysfunction has been demonstrated and human induced pluripotent stem cell-derived blood-brain barrier models have suggested the putative molecular mechanisms of pathological blood-brain barrier. In this review, we summarize recent evidence of blood-brain barrier dysfunction in Alzheimer’s disease from pathological analyses, imaging studies, animal models, and stem cell sources. Additionally, we discuss the potential future directions for blood-brain barrier research. Related Articles | Metrics

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NADPH oxidase 4 (NOX4) as a biomarker and therapeutic target in neurodegenerative diseases Napissara Boonpraman, Sun Shin Yi 2024, 19 (9):  1961-1966.  doi: 10.4103/1673-5374.390973 Abstract ( 134 )   PDF (1369KB) ( 85 )   Save Diseases like Alzheimer’s and Parkinson’s diseases are defined by inflammation and the damage neurons undergo due to oxidative stress. A primary reactive oxygen species contributor in the central nervous system, NADPH oxidase 4, is viewed as a potential therapeutic touchstone and indicative marker for these ailments. This in-depth review brings to light distinct features of NADPH oxidase 4, responsible for generating superoxide and hydrogen peroxide, emphasizing its pivotal role in activating glial cells, inciting inflammation, and disturbing neuronal functions. Significantly, malfunctioning astrocytes, forming the majority in the central nervous system, play a part in advancing neurodegenerative diseases, due to their reactive oxygen species and inflammatory factor secretion. Our study reveals that aiming at NADPH oxidase 4 within astrocytes could be a viable treatment pathway to reduce oxidative damage and halt neurodegenerative processes. Adjusting NADPH oxidase 4 activity might influence the neuroinflammatory cytokine levels, including myeloperoxidase and osteopontin, offering better prospects for conditions like Alzheimer’s disease and Parkinson’s disease. This review sheds light on the role of NADPH oxidase 4 in neural degeneration, emphasizing its drug target potential, and paving the path for novel treatment approaches to combat these severe conditions. Related Articles | Metrics

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Circadian rhythm disruption and retinal dysfunction: a bidirectional link in Alzheimer’s disease? Laura Carrero, Desireé Antequera, Cristina Municio, Eva Carro 2024, 19 (9):  1967-1972.  doi: 10.4103/1673-5374.390962 Abstract ( 118 )   PDF (759KB) ( 53 )   Save Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer’s disease. A predominant function of the retina is circadian synchronization, carrying information to the brain through the retinohypothalamic tract, which projects to the suprachiasmatic nucleus. Notably, Alzheimer’s disease hallmarks, including amyloid-β, are present in the retinas of Alzheimer’s disease patients, followed/associated by structural and functional disturbances. However, the mechanistic link between circadian dysfunction and the pathological changes affecting the retina in Alzheimer’s disease is not fully understood, although some studies point to the possibility that retinal dysfunction could be considered an early pathological process that directly modulates the circadian rhythm.  Related Articles | Metrics

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Interplay between the glymphatic system and neurotoxic proteins in Parkinson’s disease and related disorders: current knowledge and future directions Yumei Yue, Xiaodan Zhang, Wen Lv, Hsin-Yi Lai, Ting Shen 2024, 19 (9):  1973-1980.  doi: 10.4103/1673-5374.390970 Abstract ( 133 )   PDF (2951KB) ( 79 )   Save Parkinson’s disease is a common neurodegenerative disorder that is associated with abnormal aggregation and accumulation of neurotoxic proteins, including α-synuclein, amyloid-β, and tau, in addition to the impaired elimination of these neurotoxic protein. Atypical parkinsonism, which has the same clinical presentation and neuropathology as Parkinson’s disease, expands the disease landscape within the continuum of Parkinson’s disease and related disorders. The glymphatic system is a waste clearance system in the brain, which is responsible for eliminating the neurotoxic proteins from the interstitial fluid. Impairment of the glymphatic system has been proposed as a significant contributor to the development and progression of neurodegenerative disease, as it exacerbates the aggregation of neurotoxic proteins and deteriorates neuronal damage. Therefore, impairment of the glymphatic system could be considered as the final common pathway to neurodegeneration. Previous evidence has provided initial insights into the potential effect of the impaired glymphatic system on Parkinson’s disease and related disorders; however, many unanswered questions remain. This review aims to provide a comprehensive summary of the growing literature on the glymphatic system in Parkinson’s disease and related disorders. The focus of this review is on identifying the manifestations and mechanisms of interplay between the glymphatic system and neurotoxic proteins, including loss of polarization of aquaporin-4 in astrocytic endfeet, sleep and circadian rhythms, neuroinflammation, astrogliosis, and gliosis. This review further delves into the underlying pathophysiology of the glymphatic system in Parkinson’s disease and related disorders, and the potential implications of targeting the glymphatic system as a novel and promising therapeutic strategy. Related Articles | Metrics

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Roles of neuronal lysosomes in the etiology of Parkinson’s disease Mattia Volta 2024, 19 (9):  1981-1983.  doi: 10.4103/1673-5374.390954 Abstract ( 105 )   PDF (2536KB) ( 51 )   Save Therapeutic progress in neurodegenerative conditions such as Parkinson’s disease has been hampered by a lack of detailed knowledge of its molecular etiology. The advancements in genetics and genomics have provided fundamental insights into specific protein players and the cellular processes involved in the onset of disease. In this respect, the autophagy-lysosome system has emerged in recent years as a strong point of convergence for genetics, genomics, and pathologic indications, spanning both familial and idiopathic Parkinson’s disease. Most, if not all, genes linked to familial disease are involved, in a regulatory capacity, in lysosome function (e.g., LRRK2, alpha-synuclein, VPS35, Parkin, and PINK1). Moreover, the majority of genomic loci associated with increased risk of idiopathic Parkinson’s cluster in lysosome biology and regulation (GBA as the prime example). Lastly, neuropathologic evidence showed alterations in lysosome markers in autoptic material that, coupled to the alpha-synuclein proteinopathy that defines the disease, strongly indicate an alteration in functionality. In this Brief Review article, I present a personal perspective on the molecular and cellular involvement of lysosome biology in Parkinson’s pathogenesis, aiming at a larger vision on the events underlying the onset of the disease. The attempts at targeting autophagy for therapeutic purposes in Parkinson’s have been mostly aimed at “indiscriminately” enhancing its activity to promote the degradation and elimination of aggregate protein accumulations, such as alpha-synuclein Lewy bodies. However, this approach is based on the assumption that protein pathology is the root cause of disease, while pre-pathology and pre-degeneration dysfunctions have been largely observed in clinical and pre-clinical settings. In addition, it has been reported that unspecific boosting of autophagy can be detrimental. Thus, it is important to understand the mechanisms of specific autophagy forms and, even more, the adjustment of specific lysosome functionalities. Indeed, lysosomes exert fine signaling capacities in addition to their catabolic roles and might participate in the regulation of neuronal and glial cell functions. Here, I discuss hypotheses on these possible mechanisms, their links with etiologic and risk factors for Parkinson’s disease, and how they could be targeted for disease-modifying purposes. Related Articles | Metrics

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On implications of somatostatin in diabetic retinopathy Yanhong Fang, Qionghua Wang, Youjian Li, Li Zeng, Jian Liu, Kepeng Ou 2024, 19 (9):  1984-1990.  doi: 10.4103/1673-5374.390955 Abstract ( 233 )   PDF (844KB) ( 67 )   Save Somatostatin, a naturally produced neuroprotective peptide, depresses excitatory neurotransmission and exerts anti-proliferative and anti-inflammatory effects on the retina. In this review, we summarize the progress of somatostatin treatment of diabetic retinopathy through analysis of relevant studies published from February 2019 to February 2023 extracted from the PubMed and Google Scholar databases. Insufficient neuroprotection, which occurs as a consequence of declined expression or dysregulation of retinal somatostatin in the very early stages of diabetic retinopathy, triggers retinal neurovascular unit impairment and microvascular damage. Somatostatin replacement is a promising treatment for retinal neurodegeneration in diabetic retinopathy. Numerous pre-clinical and clinical trials of somatostatin analog treatment for early diabetic retinopathy have been initiated. In one such trial (EUROCONDOR), topical administration of somatostatin was found to exert neuroprotective effects in patients with pre-existing retinal neurodysfunction, but had no impact on the onset of diabetic retinopathy. Overall, we concluded that somatostatin restoration may be especially beneficial for the growing population of patients with early-stage retinopathy. In order to achieve early prevention of diabetic retinopathy initiation, and thereby salvage visual function before the appearance of moderate non-proliferative diabetic retinopathy, several issues need to be addressed. These include the needs to: a) update and standardize the retinal screening scheme to incorporate the detection of early neurodegeneration, b) identify patient subgroups who would benefit from somatostatin analog supplementation, c) elucidate the interactions of somatostatin, particularly exogenously-delivered somatostatin analogs, with other retinal peptides in the context of hyperglycemia, and d) design safe, feasible, low cost, and effective administration routes. Related Articles | Metrics

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Therapeutic advances in neural regeneration for Huntington’s disease Francesco D’Egidio, Vanessa Castelli, Giorgia Lombardozzi, Fabrizio Ammannito, Annamaria Cimini, Michele d’Angelo 2024, 19 (9):  1991-1997.  doi: 10.4103/1673-5374.390969 Abstract ( 125 )   PDF (1972KB) ( 60 )   Save Huntington’s disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt) protein. In physiological conditions, Htt is involved in many cellular processes such as cell signaling, transcriptional regulation, energy metabolism regulation, DNA maintenance, axonal trafficking, and antiapoptotic activity. When the genetic alteration is present, the production of a mutant version of Htt (mHtt) occurs, which is characterized by a plethora of pathogenic activities that, finally, lead to cell death. Among all the cells in which mHtt exerts its dangerous activity, the GABAergic Medium Spiny Neurons seem to be the most affected by the mHtt-induced excitotoxicity both in the cortex and in the striatum. However, as the neurodegeneration proceeds ahead the neuronal loss grows also in other brain areas such as the cerebellum, hypothalamus, thalamus, subthalamic nucleus, globus pallidus, and substantia nigra, determining the variety of symptoms that characterize Huntington’s disease. From a clinical point of view, Huntington’s disease is characterized by a wide spectrum of symptoms spanning from motor impairment to cognitive disorders and dementia. Huntington’s disease shows a prevalence of around 3.92 cases every 100,000 worldwide and an incidence of 0.48 new cases every 100,000/year. To date, there is no available cure for Huntington’s disease. Several treatments have been developed so far, aiming to reduce the severity of one or more symptoms to slow down the inexorable decline caused by the disease. In this context, the search for reliable strategies to target the different aspects of Huntington’s disease become of the utmost interest. In recent years, a variety of studies demonstrated the detrimental role of neuronal loss in Huntington’s disease condition highlighting how the replacement of lost cells would be a reasonable strategy to overcome the neurodegeneration. In this view, numerous have been the attempts in several preclinical models of Huntington’s disease to evaluate the feasibility of invasive and non-invasive approaches. Thus, the aim of this review is to offer an overview of the most appealing approaches spanning from stem cell-based cell therapy to extracellular vesicles such as exosomes in light of promoting neurogenesis, discussing the results obtained so far, their limits and the future perspectives regarding the neural regeneration in the context of Huntington’s disease. Related Articles | Metrics

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The advantages of multi-level omics research on stem cell-based therapies for ischemic stroke Yiqing Wang, Chuheng Chang, Renzhi Wang, Xiaoguang Li, Xinjie Bao 2024, 19 (9):  1998-2003.  doi: 10.4103/1673-5374.390959 Abstract ( 155 )   PDF (846KB) ( 141 )   Save Stem cell transplantation is a potential therapeutic strategy for ischemic stroke. However, despite many years of preclinical research, the application of stem cells is still limited to the clinical trial stage. Although stem cell therapy can be highly beneficial in promoting functional recovery, the precise mechanisms of action that are responsible for this effect have yet to be fully elucidated. Omics analysis provides us with a new perspective to investigate the physiological mechanisms and multiple functions of stem cells in ischemic stroke. Transcriptomic, proteomic, and metabolomic analyses have become important tools for discovering biomarkers and analyzing molecular changes under pathological conditions. Omics analysis could help us to identify new pathways mediated by stem cells for the treatment of ischemic stroke via stem cell therapy, thereby facilitating the translation of stem cell therapies into clinical use. In this review, we summarize the pathophysiology of ischemic stroke and discuss recent progress in the development of stem cell therapies for the treatment of ischemic stroke by applying multi-level omics. We also discuss changes in RNAs, proteins, and metabolites in the cerebral tissues and body fluids under stroke conditions and following stem cell treatment, and summarize the regulatory factors that play a key role in stem cell therapy. The exploration of stem cell therapy at the molecular level will facilitate the clinical application of stem cells and provide new treatment possibilities for the complete recovery of neurological function in patients with ischemic stroke. Related Articles | Metrics

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Emerging role of galectin 3 in neuroinflammation and neurodegeneration Brian M. Lozinski, Khanh Ta, Yifei Dong 2024, 19 (9):  2004-2009.  doi: 10.4103/1673-5374.391181 Abstract ( 124 )   PDF (1562KB) ( 90 )   Save Neuroinflammation and neurodegeneration are key processes that mediate the development and progression of neurological diseases. However, the mechanisms modulating these processes in different diseases remain incompletely understood. Advances in single cell based multi-omic analyses have helped to identify distinct molecular signatures such as Lgals3 that is associated with neuroinflammation and neurodegeneration in the central nervous system (CNS). Lgals3 encodes galectin-3 (Gal3), a β-galactoside and glycan binding glycoprotein that is frequently upregulated by reactive microglia/macrophages in the CNS during various neurological diseases. While Gal3 has previously been associated with non-CNS inflammatory and fibrotic diseases, recent studies highlight Gal3 as a prominent regulator of inflammation and neuroaxonal damage in the CNS during diseases such as multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease. In this review, we summarize the pleiotropic functions of Gal3 and discuss evidence that demonstrates its detrimental role in neuroinflammation and neurodegeneration during different neurological diseases. We also consider the challenges of translating preclinical observations into targeting Gal3 in the human CNS.  Related Articles | Metrics

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Exosomes derived from microglia overexpressing miR-124-3p alleviate neuronal endoplasmic reticulum stress damage after repetitive mild traumatic brain injury  Yan Wang, Dai Li, Lan Zhang, Zhenyu Yin, Zhaoli Han, Xintong Ge, Meimei Li, Jing Zhao, Shishuang Zhang, Yan Zuo, Xiangyang Xiong, Han Gao, Qiang Liu, Fanglian Chen, Ping Lei 2024, 19 (9):  2010-2018.  doi: 10.4103/1673-5374.391189 Abstract ( 230 )   PDF (4815KB) ( 78 )   Save We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury. However, its impact on neuronal endoplasmic reticulum stress following repetitive mild traumatic brain injury remains unclear. In this study, we first used an HT22 scratch injury model to mimic traumatic brain injury, then co-cultured the HT22 cells with BV2 microglia expressing high levels of miR-124-3p. We found that exosomes containing high levels of miR-124-3p attenuated apoptosis and endoplasmic reticulum stress. Furthermore, luciferase reporter assay analysis confirmed that miR-124-3p bound specifically to the endoplasmic reticulum stress-related protein IRE1α, while an IRE1α functional salvage experiment confirmed that miR-124-3p targeted IRE1α and reduced its expression, thereby inhibiting endoplasmic reticulum stress in injured neurons. Finally, we delivered microglia-derived exosomes containing miR-124-3p intranasally to a mouse model of repetitive mild traumatic brain injury and found that endoplasmic reticulum stress and apoptosis levels in hippocampal neurons were significantly reduced. These findings suggest that, after repetitive mild traumatic brain injury, miR-124-3 can be transferred from microglia-derived exosomes to injured neurons, where it exerts a neuroprotective effect by inhibiting endoplasmic reticulum stress. Therefore, microglia-derived exosomes containing miR-124-3p may represent a novel therapeutic strategy for repetitive mild traumatic brain injury. Related Articles | Metrics

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The action mechanism by which C1q/tumor necrosis factor-related protein-6 alleviates cerebral ischemia/reperfusion injury in diabetic mice Bo Zhao, Mei Li, Bingyu Li, Yanan Li, Qianni Shen, Jiabao Hou, Yang Wu, Lijuan Gu, Wenwei Gao 2024, 19 (9):  2019-2026.  doi: 10.4103/1673-5374.390951 Abstract ( 91 )   PDF (1940KB) ( 56 )   Save Studies have shown that C1q/tumor necrosis factor-related protein-6 (CTRP6) can alleviate renal ischemia/reperfusion injury in mice. However, its role in the brain remains poorly understood. To investigate the role of CTRP6 in cerebral ischemia/reperfusion injury associated with diabetes mellitus, a diabetes mellitus mouse model of cerebral ischemia/reperfusion injury was established by occlusion of the middle cerebral artery. To overexpress CTRP6 in the brain, an adeno-associated virus carrying CTRP6 was injected into the lateral ventricle. The result was that oxygen injury and inflammation in brain tissue were clearly attenuated, and the number of neurons was greatly reduced. In vitro experiments showed that CTRP6 knockout exacerbated oxidative damage, inflammatory reaction, and apoptosis in cerebral cortical neurons in high glucose hypoxia-simulated diabetic cerebral ischemia/reperfusion injury. CTRP6 overexpression enhanced the sirtuin-1 signaling pathway in diabetic brains after ischemia/reperfusion injury. To investigate the mechanism underlying these effects, we examined mice with depletion of brain tissue-specific sirtuin-1. CTRP6-like protection was achieved by activating the sirtuin-1 signaling pathway. Taken together, these results indicate that CTRP6 likely attenuates cerebral ischemia/reperfusion injury through activation of the sirtuin-1 signaling pathway. Related Articles | Metrics

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Transplantation of human placental chorionic plate-derived mesenchymal stem cells for repair of neurological damage in neonatal hypoxic-ischemic encephalopathy Lulu Xue, Ruolan Du, Ning Bi, Qiuxia Xiao, Yifei Sun, Ruize Niu, Yaxin Tan, Li Chen, Jia Liu, Tinghua Wang, Liulin Xiong 2024, 19 (9):  2027-2035.  doi: 10.4103/1673-5374.390952 Abstract ( 111 )   PDF (5558KB) ( 37 )   Save Neonatal hypoxic-ischemic encephalopathy is often associated with permanent cerebral palsy, neurosensory impairments, and cognitive deficits, and there is no effective treatment for complications related to hypoxic-ischemic encephalopathy. The therapeutic potential of human placental chorionic plate-derived mesenchymal stem cells for various diseases has been explored. However, the potential use of human placental chorionic plate-derived mesenchymal stem cells for the treatment of neonatal hypoxic-ischemic encephalopathy has not yet been investigated. In this study, we injected human placental chorionic plate-derived mesenchymal stem cells into the lateral ventricle of a neonatal hypoxic-ischemic encephalopathy rat model and observed significant improvements in both cognitive and motor function. Protein chip analysis showed that interleukin-3 expression was significantly elevated in neonatal hypoxic-ischemic encephalopathy model rats. Following transplantation of human placental chorionic plate-derived mesenchymal stem cells, interleukin-3 expression was downregulated. To further investigate the role of interleukin-3 in neonatal hypoxic-ischemic encephalopathy, we established an in vitro SH-SY5Y cell model of hypoxic-ischemic injury through oxygen-glucose deprivation and silenced interleukin-3 expression using small interfering RNA. We found that the activity and proliferation of SH-SY5Y cells subjected to oxygen-glucose deprivation were further suppressed by interleukin-3 knockdown. Furthermore, interleukin-3 knockout exacerbated neuronal damage and cognitive and motor function impairment in rat models of hypoxic-ischemic encephalopathy. The findings suggest that transplantation of hpcMSCs ameliorated behavioral impairments in a rat model of hypoxic-ischemic encephalopathy, and this effect was mediated by interleukin-3-dependent neurological function. Related Articles | Metrics

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Effects of Lycium barbarum polysaccharide on cytokines in adolescents with subthreshold depression: a randomized controlled study Xiaoyue Li, Tao Liu, Xuan Mo, Runhua Wang, Xueyan Kong, Robin Shao, Roger S. McIntyre, Kwok-Fai So, Kangguang Lin 2024, 19 (9):  2036-2040.  doi: 10.4103/1673-5374.389360 Abstract ( 190 )   PDF (1360KB) ( 99 )   Save Strong evidence has accumulated to show a correlation between depression symptoms and inflammatory responses. Moreover, anti-inflammatory treatment has shown partial effectiveness in alleviating depression symptoms. Lycium barbarum polysaccharide (LBP), derived from Goji berries, exhibits notable antioxidative and anti-inflammatory properties. In our recent double-blinded randomized placebo-controlled trial, we found that LBP significantly reduced depressive symptoms in adolescents with subthreshold depression. It is presumed that the antidepressant effect of LBP may be associated with its influence on inflammatory cytokines. In the double-blinded randomized controlled trial, we enrolled 29 adolescents with subthreshold depression and randomly divided them into an LBP group and a placebo group. In the LBP group, adolescents were given 300 mg/d LBP. A 6-week follow up was completed by 24 adolescents, comprising 14 adolescents from the LBP group (15.36 ± 2.06 years, 3 men and 11 women) and 10 adolescents from the placebo group (14.9 ± 1.6 years, 2 men and 8 women). Our results showed that after 6 weeks of treatment, the interleukin-17A level in the LBP group was lower than that in the placebo group. Network analysis showed that LBP reduced the correlations and connectivity between inflammatory factors, which were associated with the improvement in depressive symptoms. These findings suggest that 6-week administration of LBP suppresses the immune response by reducing interleukin-17A level, thereby exerting an antidepressant effect. Related Articles | Metrics

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Metformin alleviates spinal cord injury by inhibiting nerve cell ferroptosis through upregulation of heme oxygenase-1 expression Zhihua Wang, Wu Zhou, Zhixiong Zhang, Lulu Zhang, Meihua Li 2024, 19 (9):  2041-2049.  doi: 10.4103/1673-5374.390960 Abstract ( 142 )   PDF (43925KB) ( 117 )   Save Previous studies have reported upregulation of heme oxygenase-1 in different central nervous system injury models. Heme oxygenase-1 plays a critical anti-inflammatory role and is essential for regulating cellular redox homeostasis. Metformin is a classic drug used to treat type 2 diabetes that can inhibit ferroptosis. Previous studies have shown that, when used to treat cardiovascular and digestive system diseases, metformin can also upregulate heme oxygenase-1 expression. Therefore, we hypothesized that heme oxygenase-1 plays a significant role in mediating the beneficial effects of metformin on neuronal ferroptosis after spinal cord injury. To test this, we first performed a bioinformatics analysis based on the GEO database and found that heme oxygenase-1 was upregulated in the lesion of rats with spinal cord injury. Next, we confirmed this finding in a rat model of T9 spinal cord compression injury that exhibited spinal cord nerve cell ferroptosis. Continuous intraperitoneal injection of metformin for 14 days was found to both upregulate heme oxygenase-1 expression and reduce neuronal ferroptosis in rats with spinal cord injury. Subsequently, we used a lentivirus vector to knock down heme oxygenase-1 expression in the spinal cord, and found that this significantly reduced the effect of metformin on ferroptosis after spinal cord injury. Taken together, these findings suggest that metformin inhibits neuronal ferroptosis after spinal cord injury, and that this effect is partially dependent on upregulation of heme oxygenase-1. Related Articles | Metrics

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Biochanin A attenuates spinal cord injury in rats during early stages by inhibiting oxidative stress and inflammasome activation Xigong Li, Jing Fu, Ming Guan, Haifei Shi, Wenming Pan, Xianfeng Lou 2024, 19 (9):  2050-2056.  doi: 10.4103/1673-5374.390953 Abstract ( 130 )   PDF (35504KB) ( 37 )   Save Previous studies have shown that Biochanin A, a flavonoid compound with estrogenic effects, can serve as a neuroprotective agent in the context of cerebral ischemia/reperfusion injury; however, its effect on spinal cord injury is still unclear. In this study, a rat model of spinal cord injury was established using the heavy object impact method, and the rats were then treated with Biochanin A (40 mg/kg) via intraperitoneal injection for 14 consecutive days. The results showed that Biochanin A effectively alleviated spinal cord neuronal injury and spinal cord tissue injury, reduced inflammation and oxidative stress in spinal cord neurons, and reduced apoptosis and pyroptosis. In addition, Biochanin A inhibited the expression of inflammasome-related proteins (ASC, NLRP3, and GSDMD) and the Toll-like receptor 4/nuclear factor-κB pathway, activated the Nrf2/heme oxygenase 1 signaling pathway, and increased the expression of the autophagy markers LC3 II, Beclin-1, and P62. Moreover, the therapeutic effects of Biochanin A on early post-spinal cord injury were similar to those of methylprednisolone. These findings suggest that Biochanin A protected neurons in the injured spinal cord through the Toll-like receptor 4/nuclear factor κB and Nrf2/heme oxygenase 1 signaling pathways. These findings suggest that Biochanin A can alleviate post-spinal cord injury at an early stage. Related Articles | Metrics

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Unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neuropathology and behavioral deficits in parkinsonian rats with α-synucleinopathy Bismark Gatica-Garcia, Michael J. Bannon, Irma Alicia Martínez-Dávila, Luis O. Soto-Rojas, David Reyes-Corona, Lourdes Escobedo, Minerva Maldonado-Berny, ME Gutierrez-Castillo, Armando J. Espadas-Alvarez, Manuel A. Fernandez-Parrilla, Juan U. Mascotte-Cruz, CP Rodríguez-Oviedo, Irais E. Valenzuela-Arzeta, Claudia Luna-Herrera, Francisco E. Lopez-Salas, Jaime Santoyo-Salazar, Daniel Martinez-Fong 2024, 19 (9):  2057-2067.  doi: 10.4103/1673-5374.391190 Abstract ( 120 )   PDF (109214KB) ( 26 )   Save Parkinsonism by unilateral, intranigral β-sitosterol β-D-glucoside administration in rats is distinguished in that the α-synuclein insult begins unilaterally but spreads bilaterally and increases in severity over time, thus replicating several clinical features of Parkinson’s disease, a typical α-synucleinopathy. As Nurr1 represses α-synuclein, we evaluated whether unilateral transfected of rNurr1-V5 transgene via neurotensin-polyplex to the substantia nigra on day 30 after unilateral β-sitosterol β-D-glucoside lesion could affect bilateral neuropathology and sensorimotor deficits on day 30 post-transfection. This study found that rNurr1-V5 expression but not that of the green fluorescent protein (the negative control) reduced β-sitosterol β-D-glucoside-induced neuropathology. Accordingly, a bilateral increase in tyrosine hydroxylase-positive cells and arborization occurred in the substantia nigra and increased tyrosine hydroxylase-positive ramifications in the striatum. In addition, tyrosine hydroxylase-positive cells displayed less senescence marker β-galactosidase and more neuron-cytoskeleton marker βIII-tubulin and brain-derived neurotrophic factor. A significant decrease in activated microglia (positive to ionized calcium-binding adaptor molecule 1) and neurotoxic astrocytes (positive to glial fibrillary acidic protein and complement component 3) and increased neurotrophic astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10) also occurred in the substantia nigra. These effects followed the bilateral reduction in α-synuclein aggregates in the nigrostriatal system, improving sensorimotor behavior. Our results show that unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neurodegeneration (senescence and loss of neuron-cytoskeleton and tyrosine hydroxylase-positive cells), neuroinflammation (activated microglia, neurotoxic astrocytes), α-synuclein aggregation, and sensorimotor deficits. Increased neurotrophic astrocytes and brain-derived neurotrophic factor can mediate the rNurr1-V5 effect, supporting its potential clinical use in the treatment of Parkinson’s disease. Related Articles | Metrics

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Resilience to structural and molecular changes in excitatory synapses in the hippocampus contributes to cognitive function recovery in Tg2576 mice Carolina Aguado, Sara Badesso, José Martínez-Hernández, †, Alejandro Martín-Belmonte, Rocío Alfaro-Ruiz, Miriam Fernández, Ana Esther Moreno-Martínez, Mar Cuadrado-Tejedor, Ana García-Osta, Rafael Luján 2024, 19 (9):  2068-2074.  doi: 10.4103/1673-5374.390963 Abstract ( 141 )   PDF (3277KB) ( 45 )   Save Plaques of amyloid-β (Aβ) and neurofibrillary tangles are the main pathological characteristics of Alzheimer’s disease (AD). However, some older adult people with AD pathological hallmarks can retain cognitive function. Unraveling the factors that lead to this cognitive resilience to AD offers promising prospects for identifying new therapeutic targets. Our hypothesis focuses on the contribution of resilience to changes in excitatory synapses at the structural and molecular levels, which may underlie healthy cognitive performance in aged AD animals. Utilizing the Morris Water Maze test, we selected resilient (asymptomatic) and cognitively impaired aged Tg2576 mice. While the enzyme-linked immunosorbent assay showed similar levels of Aβ42 in both experimental groups, western blot analysis revealed differences in tau pathology in the pre-synaptic supernatant fraction. To further investigate the density of synapses in the hippocampus of 16–18 month-old Tg2576 mice, we employed stereological and electron microscopic methods. Our findings indicated a decrease in the density of excitatory synapses in the stratum radiatum of the hippocampal CA1 in cognitively impaired Tg2576 mice compared with age-matched resilient Tg2576 and non-transgenic controls. Intriguingly, through quantitative immunoelectron microscopy in the hippocampus of impaired and resilient Tg2576 transgenic AD mice, we uncovered differences in the subcellular localization of glutamate receptors. Specifically, the density of GluA1, GluA2/3, and mGlu5 in spines and dendritic shafts of CA1 pyramidal cells in impaired Tg2576 mice was significantly reduced compared with age-matched resilient Tg2576 and non-transgenic controls. Notably, the density of GluA2/3 in resilient Tg2576 mice was significantly increased in spines but not in dendritic shafts compared with impaired Tg2576 and non-transgenic mice. These subcellular findings strongly support the hypothesis that dendritic spine plasticity and synaptic machinery in the hippocampus play crucial roles in the mechanisms of cognitive resilience in Tg2576 mice. Related Articles | Metrics

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Magnetic resonance-guided focused ultrasound for essential tremor: a prospective, single center, single-arm study Rui Zong, Xuemei Li, Chunyu Yin, Jianfeng He, Dekang Zhang, Xiangbing Bian, Lichao Huang, Jiayou Zhou, Zhipei Ling, Lin Ma, Xin Lou, Longsheng Pan, Xinguang Yu 2024, 19 (9):  2075-2080.  doi: 10.4103/1673-5374.391192 Abstract ( 560 )   PDF (4659KB) ( 73 )   Save The safety and effectiveness of magnetic resonance-guided focused ultrasound thalamotomy has been broadly established and validated for the treatment of essential tremor. In 2018, the first magnetic resonance-guided focused ultrasound system in Chinese mainland was installed at the First Medical Center of the PLA General Hospital. This prospective, single center, open-label, single-arm study was part of a worldwide prospective multicenter clinical trial (ClinicalTrials.gov Identifier: NCT03253991) conducted to confirm the safety and efficacy of magnetic resonance-guided focused ultrasound for treating essential tremor in the local population. From 2019 to 2020, 10 patients with medication refractory essential tremor were recruited into this open-label, single arm study. The treatment efficacy was determined using the Clinical Rating Scale for Tremor. Safety was evaluated according to the incidence and severity of adverse events. All of the subjects underwent a unilateral thalamotomy targeting the ventral intermediate nucleus. At the baseline assessment, the estimated marginal mean of the Clinical Rating Scale for Tremor total score was 58.3 ± 3.6, and this improved after treatment to 23.1 ± 6.4 at a 12-month follow-up assessment. A total of 50 adverse events were recorded, and 2 were defined as serious. The most common intraoperative adverse events were nausea and headache. The most frequent postoperative adverse events were paresthesia and equilibrium disorder. Most of the adverse events were mild and usually disappeared within a few days. Our findings suggest that magnetic resonance-guided focused ultrasound for the treatment of essential tremor is effective, with a good safety profile, for patients in Chinese mainland.  Related Articles | Metrics

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Gut microbiota dysbiosis contributes to α-synuclein-related pathology associated with C/EBPβ/AEP signaling activation in a mouse model of Parkinson’s disease Xiaoli Fang, Sha Liu, Bilal Muhammad, Mingxuan Zheng, Xing Ge, Yan Xu, Shu Kan, Yang Zhang, Yinghua Yu, Kuiyang Zheng, Deqin Geng, Chun-Feng Liu 2024, 19 (9):  2081-2088.  doi: 10.4103/1673-5374.391191 Abstract ( 172 )   PDF (1742KB) ( 169 )   Save Parkinson’s disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction. Gastrointestinal dysfunction can precede the onset of motor symptoms by several years. Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson’s disease, whether it plays a causal role in motor dysfunction, and the mechanism underlying this potential effect, remain unknown. CCAAT/enhancer binding protein β/asparagine endopeptidase (C/EBPβ/AEP) signaling, activated by bacterial endotoxin, can promote α-synuclein transcription, thereby contributing to Parkinson’s disease pathology. In this study, we aimed to investigate the role of the gut microbiota in C/EBPβ/AEP signaling, α-synuclein-related pathology, and motor symptoms using a rotenone-induced mouse model of Parkinson’s disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation. We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier, as well as activation of the C/EBP/AEP pathway, α-synuclein aggregation, and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits. However, treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics. Importantly, we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits, intestinal inflammation, and endotoxemia. Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits, intestinal inflammation, endotoxemia, and intestinal barrier impairment. These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits, C/EBPβ/AEP signaling activation, and α-synuclein-related pathology in a rotenone-induced mouse model of Parkinson’s disease. Additionally, our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson’s disease. Related Articles | Metrics