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15 May 2024, Volume 19 Issue 5 Previous Issue   

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From the dust: extracellular vesicles as regulators of development and neuroregeneration Leon G. Coleman Jr 2024, 19 (5):  933-934.  doi: 10.4103/1673-5374.382243 Abstract ( 92 )   PDF (1027KB) ( 41 )   Save First impressions can have a lasting impact. In science, this can be especially problematic, because our lack of understanding often causes us to mislabel and thus ignore important biological processes. In this vein, extracellular vesicles (EVs) were once considered to be “cellular dust”. Similar to the previous concept of “junk DNA” to describe protein non-coding regions, EVs are far more than just cellular dust. In fact, EVs are emerging as key mediators of intracellular communication across nearly all biological systems. This includes peripheral immune responses (e.g., arthropathies and sepsis), intra-organ communication (Seim et al., 2023), and a host of other physiological and pathological states (Figure 1A and B). EV signaling is multi-faceted due to the diverse assortment of cargo (protein, lipid, nucleic acids) and surface molecules (bioactive lipids, cell surface markers, proteins) (Tricarico et al., 2017). This allows for the communication of complex biological signals that are needed to regulate complex biological processes. Unfortunately, EVs are still often overlooked. EV surface proteins play critical roles as do content within EVs. The encapsulation of internal EV cargo by their lipid membranes can preclude the identification of EV contents if EVs are not specifically isolated or lysed prior to assessment. Thus, it is easy to miss key mediators in EVs. Ignoring the role of EVs across biological processes can lead to missed discoveries, and slow the advancement of research and therapeutics. Related Articles | Metrics

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Targeting epidermal growth factor receptor signaling to facilitate cortical injury repair? Ricardo Gómez-Oliva, Pedro Nunez-Abades, Carmen Castro 2024, 19 (5):  935-936.  doi: 10.4103/1673-5374.385291 Abstract ( 64 )   PDF (581KB) ( 33 )   Save The existence of neural stem cells (NSC) in specific areas of the adult mammalian brain leads to the generation of new neurons involved in homeostatic mechanisms. This is the case of the NSC of the subventricular zone (SVZ) that produces olfactory bulb (OB) neurons. These neurons integrate into circuits to modulate sensory information and participate in olfactory processing (Bragado Alonso et al., 2019). A series of hierarchical events need to take place to produce OB neurons from NSC of the SVZ. First, the activation of quiescent NSC is necessary to produce intermediate transit amplifying progenitors (TAP), which will generate neuroblasts. The latter are cells that maintain a proliferative phenotype while in an immature phase. However, once they initiate migration toward the OB, they progressively undergo their differentiation into neurons (Kjell et al., 2020). Related Articles | Metrics

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Beyond functional MRI signals: molecular and cellular modifiers of the functional connectome and cognition Lorenzo Pini, Alessandro Salvalaggio, Maurizio Corbetta 2024, 19 (5):  937-938.  doi: 10.4103/1673-5374.385292 Abstract ( 96 )   PDF (876KB) ( 97 )   Save Our brain is constantly active. Even at rest, the brain carries out essential functions such as maintenance of resting potentials, subthreshold synaptic activity, and spiking activity related to information processing. This resting activity can be assessed with several in vivo tools, such as resting-state functional magnetic resonance imaging. This technique measures subtle changes in blood flow, volume, and oxygenation that occur over time. Although vascular in nature, resting-state functional magnetic resonance imaging is considered a reliable proxy of neural activity and several studies have shown that the brain is functionally divided into interacting neural networks called the “functional connectome”.  Related Articles | Metrics

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Alpha7 nicotinic receptors as potential theranostic targets for experimental stroke Maider Garbizu, Laura Aguado, Abraham Martín 2024, 19 (5):  939-940.  doi: 10.4103/1673-5374.385294 Abstract ( 78 )   PDF (528KB) ( 45 )   Save Inflammatory reflex and cholinergic anti-inflammatory pathway: Innate immune system triggers a local inflammatory response following an injury or a pathogen invasion. Likewise, this inflammatory response is limited by rapid, localized, and adaptive anti-inflammatory responses which are crucial for maintaining homeostasis. Hence, the loss of these responses converts a limited and protective inflammatory response into an excessive and harmful response. Anti-inflammatory responses are integrated into the central nervous system, since the central nervous system accumulates information about harmful events, activates defenses, and builds memory for survival. At the same time, it has been demonstrated that hypothalamic neuronal signaling can be altered by inflammation in peripheral tissues. Additionally, immune cells release neuropeptides and neurotransmitters such as acetylcholine (ACh), the main neurotransmitter of the parasympathetic autonomic nervous system, evidencing the communication between the immune and nervous systems (Tracey, 2002).  Related Articles | Metrics

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Targeting autophagy by polyphenols to prevent glycative stress-toxicity in the brain Alejandro Ponce-Mora, Eloy Bejarano 2024, 19 (5):  941-942.  doi: 10.4103/1673-5374.385295 Abstract ( 71 )   PDF (2422KB) ( 29 )   Save Glycative stress – a pathological hub in brain dysfunction: The nervous system is an intricate network that requires precise and complex maintenance. In recent years, growing evidence highlights the detrimental impact of glycative stress on brain homeostasis, which disables a network of vital processes, necessary for optimal function (Gómez et al., 2021). Related Articles | Metrics

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Neurological consequences of human calmodulin mutations Helene H. Jensen, Anders Olsen 2024, 19 (5):  943-944.  doi: 10.4103/1673-5374.385299 Abstract ( 54 )   PDF (377KB) ( 33 )   Save When calcium ions enter the cytosol, it is a stimulatory signal for cellular events. The calcium sensor calmodulin picks up the change in calcium concentration and relays this information to its more than 300 downstream interaction partners. In this way, calmodulin affects cellular processes such as fertilization, muscle contraction, neuronal firing, and apoptosis. That is, calmodulin is involved in (nearly) everything! The significance of calmodulin is emphasized by the fact that we all carry three different genes (CALM1,2,3) on different chromosomes that encode the exact same calmodulin protein, and these are all expressed in all cell types. Moreover, throughout vertebrate evolution, the protein sequence has remained completely unchanged. Related Articles | Metrics

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Does photobiomodulation require glucose to work effectively? Jaimie Hoh Kam, John Mitrofanis 2024, 19 (5):  945-946.  doi: 10.4103/1673-5374.385290 Abstract ( 68 )   PDF (2665KB) ( 27 )   Save A main requirement for cells to function normally is the availability of glucose. Glucose, available either direct from circulation or storage, is converted to the essential energy that cells need to drive critical intrinsic functions. If cells are deprived of glucose, they become dysfunctional and suffer distress. Photobiomodulation, the use of specific wavelengths of light on body tissues, has been shown to promote, through small organelles called mitochondria, the metabolism of glucose to make energy for cells; this energy can be used to improve cell function and survival. In this perspective, we hypothesize that the availability of glucose is central to the core mechanism of photobiomodulation; that photobiomodulation is at its most efficient in stimulating mitochondrial activity and improving cell function when there is glucose readily available. Related Articles | Metrics

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Perspectives in human brain plasticity sparked by glioma invasion: from intraoperative (re)mappings to neural reconfigurations Sam Ng, Hugues Duffau, Guillaume Herbet 2024, 19 (5):  947-948.  doi: 10.4103/1673-5374.382246 Abstract ( 95 )   PDF (1852KB) ( 108 )   Save Exploring the aptitude of the human brain to compensate functional consequences of a lesion damaging its structural architecture is a key challenge to improve patient care in various neurological diseases, to optimize neuroscientifically-informed strategies of postlesional rehabilitation, and ultimately to develop innovative neuro-regenerative therapies. The term ‘plasticity’, initially referring to the intrinsic propensity of neurons to modulate their synaptic transmission in a learning situation, was progressively transposed to brain injury research and clinical neurosciences. Indeed, in the event of brain damage, adaptive mechanisms of compensation allow a partial reshaping of the structure and activities of the central nervous system, thus permitting to some extent the maintenance of brain functions. Such findings have been observed in multiple clinical conditions, most notably in the context of diffuse low-grade gliomas (DLGGs) - a histopathological subgroup of slow-growing tumors that biologically integrates within the surrounding brain tissue, both at the synaptic (Venkatesh et al., 2019) and macro-structural levels (Numan et al., 2022). Contrary to acute neurological injuries such as stroke, where neurological recovery generally remains limited, patients with DLGGs can usually benefit from an extensive surgical excision without suffering from permanent neurological or cognitive deficits as long as critical neural structures are preserved thanks to modern intraoperative awake cognitive mapping (Lemaitre et al., 2022). Therefore, DLGGs may be viewed as a relevant model to grasp the neuroplastic mechanisms being deployed to counterbalance neuronal losses and to establish the neural fingerprints predictive of functional recovery in a lesion context. In this perspective article, the authors aimed to emphasize recent contributions investigating human brain plasticity in reaction to DLGG invasion. First, long-range axono-cortical connections are discussed as major substrates underlying spatial redeployments of brain functions. Second, the time-dependent and evolving aspects of cortical rewiring are reviewed in light of recent intraoperative direct electrical stimulation (DES) findings. Third, these spatiotemporal patterns are examined under the scope of global reconfigurations of the meta-networking brain, an emerging theory of brain functioning. Finally, a tentative dynamic and multilevel model of glioma-induced plasticity is proposed to pave the way to future research perspectives in the field. Related Articles | Metrics

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Anti-aquaporin-4 antibody (AQP4-IgG) and anti-myelin oligodendrocyte glycoprotein antibody (MOG-IgG) in the cerebrospinal fluid Tetsuya Akaishi, Tatsuro Misu 2024, 19 (5):  949-950.  doi: 10.4103/1673-5374.385293 Abstract ( 95 )   PDF (859KB) ( 18 )   Save In the last decade, a new neurological disease concept known as anti-myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated disease (MOGAD) has emerged and is currently one of the most focused research areas in the field of neuroimmunology. MOG is a membrane protein mainly expressed on the surface of oligodendrocytes (Zhou et al., 2006). The exact pathogenic role of MOG-IgG in patients with MOGAD remains unclear; however, MOG-IgG has been suggested to cause tissue alterations and damage MOG-expressing cells (Zhou et al., 2006). The pathogenicity of MOG-IgG is further supported by the observation that only a few patients with acquired central nervous system (CNS) demyelinating syndromes exhibit both anti-aquaporin-4 antibody (AQP4-IgG) and MOG-IgG simultaneously, particularly with clear positivity levels of these antibodies as indicated by a cell-based assay result with a titer ≥ 1:100 (Sechi et al., 2021; Banwell et al., 2023). Currently, MOGAD is considered a disease group distinct from multiple sclerosis (MS) or AQP4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD). Compared with patients with AQP4-IgG-positive NMOSD, patients with MOGAD are considered to have a lower relapse rate and milder neurological sequelae. In contrast to patients with AQP4-IgG-positive NMOSD, patients with MOGAD may not necessarily require long-term relapse-prevention treatment unless they show a highly active relapsing clinical course. The benefit of repeated monitoring of serum MOG-IgG titers in patients with MOGAD remains unclear and needs to be evaluated in the future. Related Articles | Metrics

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Autophagy in neuroinflammation after traumatic brain injury Chinmoy Sarkar, Marta M. Lipinski 2024, 19 (5):  951-952.  doi: 10.4103/1673-5374.382247 Abstract ( 88 )   PDF (501KB) ( 41 )   Save Traumatic brain injury (TBI) is an acquired injury of the brain caused by the impact of external forces on the brain (Maas et al., 2008). It is a major cause of death and disability among people of all ages (Maas et al., 2008). The primary mechanical injury to the brain initiates a cascade of secondary biochemical events that lead to acute and chronic neurodegeneration and activation of inflammatory pathways (Maas et al., 2008). Both brain-resident microglia and blood-derived myeloid cells – macrophages and monocytes that infiltrate the brain due to injury-induced blood-brain barrier damage, contribute to the inflammatory responses after TBI (Morganti et al., 2015). These cells are responsible for clearing the damaged tissue through phagocytosis (Henry et al., 2020). This, in turn, activates the inflammasome and interferon type-1-mediated innate immune responses (Henry et al., 2020). The initial inflammatory response is important for resolving any tissue damage as it can remove the damaged cells and clear the injured area for regeneration (Henry et al., 2020). However, this is contingent on efficient degradation of phagocytosed dead cells and tissue debris by the immune cells, and their eventual transition to anti-inflammatory states to promote tissue regeneration. In TBI, neuroinflammation persists chronically and contributes to long-term pathology and poor recovery. Related Articles | Metrics

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Use of induced pluripotent stem cell-derived brain cells, organoids, assembloids, and blood-brain barrier models in understanding alcohol and anesthetic-induced brain injuries: an emerging perspective Xiaowen Bai 2024, 19 (5):  953-954.  doi: 10.4103/1673-5374.385297 Abstract ( 74 )   PDF (473KB) ( 63 )   Save Neurological disorders, including developmental disorders, Alzheimer’s disease (AD), and psychiatric conditions, have significant social and economic impacts globally. Despite extensive research into the underlying mechanisms of these disorders, effective treatments remain elusive, partly due to the complexity of the brain, the limited availability of human brain tissue, and the blood-brain barrier (BBB)’s impermeability to certain drugs. This perspective article discusses the potential of human induced pluripotent stem cell (iPSC)-based models of brain cells, organoids, assembloids, and BBB to advance our understanding of the etiology, progression, and mechanisms of brain injuries induced by alcohol consumption and general anesthesia. These models could also be used to develop protective and therapeutic approaches. Related Articles | Metrics

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TDP-43 is a key molecule accelerating development of Alzheimer’s disease following traumatic brain injury Chu Chen 2024, 19 (5):  955-956.  doi: 10.4103/1673-5374.385301 Abstract ( 107 )   PDF (2090KB) ( 25 )   Save Currently, more than 55 million people have dementia worldwide and Alzheimer’s disease (AD) is one of the most common causes of dementia in aging. However, no effective therapies are currently available for the prevention and treatment of AD. This is largely due to our limited understanding of the mechanisms underlying the neuropathogenesis of AD. It has widely been recognized that AD is heterogeneous and that multi-factors are contributing to the pathogenesis of AD. Accumulated evidence suggests that traumatic brain injury (TBI) is an important risk factor for the development of AD and dementia later in life (Guo et al., 2000; Johnson et al., 2010). However, the precise mechanism by which TBI contributes to developing AD has yet to be elucidated.  Related Articles | Metrics

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Role of lysosomal trafficking regulator in autophagic lysosome reformation in neurons: a disease perspective Prashant Sharma, Jenny Serra-Vinardell, Wendy J. Introne, May Christine V. Malicdan 2024, 19 (5):  957-958.  doi: 10.4103/1673-5374.385298 Abstract ( 75 )   PDF (3163KB) ( 47 )   Save Lysosomes are discrete organelles that act as recycling centers for extracellular and intracellular materials, playing a pivotal role in maintaining cellular homeostasis. Their acidic environment, maintained by numerous hydrolytic enzymes, facilitates substrate degradation. Dysfunction in lysosomal processes can lead to abnormal substrate degradation, significantly impacting cellular homeostasis. High energy-demanding cells, such as post-mitotic neurons, are especially vulnerable to these changes, often resulting in neurological diseases. Autophagy, a conserved catabolic process, requires extensive lysosomal utilization. It plays a key role in removing unnecessary intracellular components, ensuring cellular homeostasis, and promoting cell survival during stress conditions such as starvation, infection, or cellular damage. Related Articles | Metrics

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Soluble alpha-synuclein post-translational modifications: unexpected regulators of pathological alpha-synuclein amplification Simran Kapila, Yuhan Sun, Chao Peng, Shujing Zhang 2024, 19 (5):  959-960.  doi: 10.4103/1673-5374.385303 Abstract ( 74 )   PDF (388KB) ( 52 )   Save The build-up of misfolded α-synuclein (α-syn) in the central nervous system is the pathological hallmark of a number of neurodegenerative diseases that are known as α-synucleinopathies. These include Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), dementia with Lewy body (LB), multiple system atrophy (MSA), and a subset of Alzheimer’s disease. Growing evidence underscores that the intercellular transmission and amplification of pathological α-syn are critical processes underlying the progression of α-synucleinopathies (Peng et al., 2020), and as such, the study of these processes could lead to the identification of promising therapeutics to mitigate disease progression. Most previous studies have focused solely on pathological seeds in relation to disease progression. However, successful amplification requires two components: the formation of pathological α-syn seeds and the transformation of soluble α-syn to the pathological conformation. The potential effects that soluble α-syn could have on pathological α-syn amplification have not been studied. Although many post-translational modifications (PTMs) have been identified on α-syn, most studies have focused on the effect of PTMs on pathological α-syn initiation, toxicity, or physiological function (He et al., 2021). However, the effects of soluble α-syn PTMs on pathological α-syn amplification remain unknown. In our recent study (Zhang et al., 2023), we focused on how PTMs on soluble α-syn regulate pathological α-syn spread in different diseases and discovered that PTMs on soluble α-syn drastically modulated pathological α-syn in different α-synucleinopathies.  Related Articles | Metrics

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New insights into the effects of APP gene dose on synapse in Down syndrome Xu-Qiao Chen, Xinxin Zuo 2024, 19 (5):  961-962.  doi: 10.4103/1673-5374.382245 Abstract ( 78 )   PDF (480KB) ( 23 )   Save Synaptic dysfunction: Alzheimer’s disease (AD) is a prevalent form of dementia, affecting over 35 million people worldwide (Tzioras et al., 2023). A synapse serves as the connection point between neurons, facilitating the transmission of information from one neuron to another. Dynamic alterations in synapses, known as synaptic plasticity, play a pivotal role in cognitive processes such as learning and memory. Synaptic loss has been identified as a key contributor to cognitive decline in AD patients. Studies have shown that the soluble forms of amyloid-beta (Aβ) and tau proteins are toxic to synapses, leading to cognitive impairment in animal models (Spires-Jones and Hyman, 2014). Additionally, the formation of oligomers of tau and Aβ can spread pathology through synaptic connections in the brain, emphasizing the vital role of synapses in disease progression. Related Articles | Metrics

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Disentangling brain PrPC proteoforms and their roles in physiology and disease Ilaria Vanni, Nonno Romolo 2024, 19 (5):  963-965.  doi: 10.4103/1673-5374.385302 Abstract ( 157 )   PDF (735KB) ( 56 )   Save The cellular prion protein (PrPC), a cell surface glycoprotein of 209 amino acids, has been considerably studied over the decades mainly due to its critical involvement in transmissible spongiform encephalopathies, or prion diseases. Indeed, it is the misfolding and aggregation of PrPC into pathological assemblies - named PrPSc – that constitute prions, the agents causing these unusual neurodegenerative diseases affecting humans and animals (Prusiner, 1982). Furthermore, increasing evidence support its relevance also in other neurodegenerative diseases (NDDs), such as Alzheimer’s and Parkinson’s diseases (Corbett et al., 2020).  Related Articles | Metrics

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Phosphorylation-driven aggregative proteins in neurodegenerative diseases: implications and therapeutics Alba Espargaró, Raimon Sabate 2024, 19 (5):  966-968.  doi: 10.4103/1673-5374.382250 Abstract ( 61 )   PDF (407KB) ( 68 )   Save Protein aggregation is related to a large number of neurodegenerative disorders. Particularly in some cases, aggregation is induced by hyperphosphorylation of a given protein. This is the case of tau, TAR DNA-binding protein 43 (TDP-43), amyloid-beta peptides (Aβ) and alpha-synuclein (α-syn), which play a key pathogenic role in Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis, among others (Tenreiro et al., 2014; Chiti and Dobson, 2017). In this perspective, we will discuss both the relationship between phosphorylation and amyloid aggregation as well as current and future therapeutic strategies aimed at inhibiting specific kinases involved in the phosphorylation step or inhibiting subsequent protein aggregation. Moreover, we will address novel approaches that are based on chemical-inducing proximity, to recruit the proteasome, the autophagy-lysosome system or specific phosphatases to degrade or dephosphorylate the target proteins. We want to focus our interest on proteolysis-targeting chimeras (PROTACs) systems, which represent one of the newest and most interesting therapeutic approaches that could be applicable to phosphorylation-driven aggregative proteins in the near future (Ciechanover and Kwon, 2015; Esposto and Martic, 2021; Jangampalli et al., 2021; Jiang et al., 2021). Related Articles | Metrics

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Perspectives for delivery of therapeutics by extravasation of biodegradable microspheres in the brain Anne-Eva van der Wijk, Ed VanBavel 2024, 19 (5):  969-970.  doi: 10.4103/1673-5374.385300 Abstract ( 55 )   PDF (4867KB) ( 34 )   Save Development of therapeutics for brain diseases has remained challenging, in particular due to the difficulty of passing the blood-brain barrier. As a result, the current arsenal of therapeutics targeting the brain is limited to small, lipid-soluble drugs and there is a lack of options for treating neuroblastomas, Alzheimer’s disease, and many other devastating pathologies. Despite the advances in strategies for crossing the blood-brain barrier such as the use of nanoparticles (Hersh et al., 2022; Duan et al., 2023), such delivery systems have not yet reached clinical practice. Therefore, novel platforms for the transport of therapeutics across the blood-brain barrier remain highly desired. This specifically holds for large molecules such as monoclonal antibodies and recombinant proteins, as well as nucleotide-based therapeutics and cell therapies. Research efforts in this field are increasing exponentially, with thousands of publications in the last few years.  Related Articles | Metrics

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Mitochondria replacement from transplanted amniotic fluid stem cells: a promising therapy for non-neuronal defects in spinal muscular atrophy Michela Pozzobon, Camilla Bean 2024, 19 (5):  971-972.  doi: 10.4103/1673-5374.385304 Abstract ( 72 )   PDF (827KB) ( 29 )   Save Spinal muscular atrophy (SMA) is a genetic disorder that primarily affects infants and leads to muscle weakness, atrophy, and paralysis. The main cause is the homozygous mutation or deletion of the SMN1 gene, resulting in inadequate levels of the survival motor neuron (SMN) protein. Approved treatments focus on restoring SMN levels through various approaches, but there is a need for “SMN-independent” therapies that target other pathological processes. Skeletal muscle is closely involved in SMA pathology, with impaired muscle function observed before motor neuron degeneration. Studies have revealed that SMN loss leads to skeletal muscle mitochondrial structural abnormalities, impaired respiration, and accumulation of reactive oxygen species. Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, have emerged as a therapeutic option due to their regenerative and immunomodulatory capabilities, including the ability to replace dysfunctional mitochondria through transcellular exchange. Amniotic fluid stem (AFS) cells are considered a favorable source for stem cell therapy due to their unique properties. By transplantation of AFS cells in a mouse model of SMN loss in the skeletal muscle we could restore mitochondrial function and correct the muscle phenotypes of SMA. Utilizing stem cell therapies to restore mitochondrial function offers promising avenues for the treatment of SMA. Related Articles | Metrics

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Is GDNF to Parkinson’s disease what BDNF is to Huntington’s disease? Francesca R. Fusco, Emanuela Paldino 2024, 19 (5):  973-974.  doi: 10.4103/1673-5374.385305 Abstract ( 76 )   PDF (1244KB) ( 35 )   Save Neurotrophic factors, or neurotrophins, are a group of molecules supporting the growth, survival, and differentiation of developing and mature neurons. Given their role in the survival of neurons, and often of specific subsets of brain cells, neurotrophins have been implicated in several ways with many neurodegenerative disorders. Related Articles | Metrics

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Protein glycation: a wolf in sweet sheep’s clothing behind neurodegeneration Ana B. Uceda, Francisco Leal-Pérez, Miquel Adrover 2024, 19 (5):  975-976.  doi: 10.4103/1673-5374.385306 Abstract ( 46 )   PDF (978KB) ( 18 )   Save At the beginning of the 16th century, Paracelsus coined the maxim: “the dose makes the poison”. This principle can be applied to all living organisms, including organs and cells. The brain and its glial and neuronal cells are no exception. Even small compounds that are essential for the life of brain cells can become truly toxic when overdosed. Related Articles | Metrics

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Assistive techniques and their added value for tremor classification in multiple sclerosis Nabin Koirala, Abdulnasir Hossen, Ioannis U. Isaias, Jens Volkmann, Muthuraman Muthuraman 2024, 19 (5):  977-978.  doi: 10.4103/1673-5374.382988 Abstract ( 51 )   PDF (841KB) ( 36 )   Save Tremor occurs in about half of multiple sclerosis (MS) patients. MS tremor has a broad frequency range of 2.5–7 Hz, with a higher prevalence of postural tremor (44%) compared to intentional tremor (6%) (Alusi et al., 2001). Tremor may affect the upper and lower extremities, head, and trunk, and may even affect the vocal cords in isolated cases of palatal tremor. MS tremor is classically attributed to lesions of the brain stem, cerebellum, or cerebellar peduncles, and tremor intensity has been shown to correlate with the number of lesions or their functional connections. However, recent work has demonstrated that inflammatory damage to the cerebello-thalamic and cortico-thalamic pathways might also play an important role in causing tremor, as it co-occurs with other signs and symptoms of MS such as dysarthria, dysmetria, dysdiadochokinesia, and dystonia (Alusi et al., 2001).  Related Articles | Metrics

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Focusing on the tetra-partite synapse in Parkinson’s disease research using human patient-derived neurons Diogo Cordeiro, Tchelet Stern, Shani Stern 2024, 19 (5):  979-981.  doi: 10.4103/1673-5374.382235 Abstract ( 81 )   PDF (1255KB) ( 40 )   Save Parkinson’s disease (PD) was first described as a neurological disease by Dr. James Parkinson in 1817 as a “shaking palsy”. Since that time, much more is known about the pathophysiology of PD yet the disease is still uncurable. The hallmark of the disease is often considered Lewy body neural inclusions in the substantia nigra pars compacta and other brain areas, although not all patients have these inclusions. The patients exhibit massive neuronal cell loss in the substantia nigra pars compacta, which is associated with the motor symptoms of tremor, bradykinesia, rigidity, and postural instability. PD is the second most common neurodegenerative disease after Alzheimer’s disease with a prevalence of around 1% of individuals over the age of 60. PD is a progressive and incurable disease with other non-motor symptoms, sometimes prodromal, such as depression, impaired olfaction, constipation, urinary dysfunction, decreased respiratory muscle strength, and more. Animal in vivo models have been widely used to study PD. However, their limitations include species differences and the inability to fully replicate human disease, especially the sporadic forms of the disease.  Human induced pluripotent stem cells (iPSCs) offer the potential to generate patient-specific neurons that can recapitulate disease-specific phenotypes. This approach enabled the discovery of some pathophysiological mechanisms, gene dysregulation, affected pathways, and electrophysiological differences in neurons of neurodevelopmental, neuropsychiatric, and neurodegenerative disorders (Schafer et al., 2019; Stern et al., 2023). Related Articles | Metrics

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Two become one: combination of two risk factors in a new glaucoma animal model Nils Kluge, Sabrina Reinehr 2024, 19 (5):  982-983.  doi: 10.4103/1673-5374.385289 Abstract ( 54 )   PDF (3131KB) ( 29 )   Save https://orcid.org/0000-0002-4770-0210 (Sabrina Reinehr) Related Articles | Metrics

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Astrocytic calcium waves: unveiling their roles in sleep and arousal modulation Erxi Wu, Dan Qi, Damir Nizamutdinov, Jason H. Huang 2024, 19 (5):  984-987.  doi: 10.4103/1673-5374.385287 Abstract ( 99 )   PDF (775KB) ( 56 )   Save Neuron-astrocyte interactions are vital for the brain’s connectome. Understanding astrocyte activities is crucial for comprehending the complex neural network, particularly the population-level functions of neurons in different cortical states and associated behaviors in mammals. Studies on animal sleep and wakefulness have revealed distinct cortical synchrony patterns between neurons. Astrocytes, outnumbering neurons by nearly fivefold, support and regulate neuronal and synaptic function. Recent research on astrocyte activation during cortical state transitions has emphasized the influence of norepinephrine as a neurotransmitter and calcium waves as key components of ion channel signaling. This summary focuses on a few recent studies investigating astrocyte-neuron interactions in mouse models during sleep, wakefulness, and arousal levels, exploring the involvement of noradrenaline signaling, ion channels, and glutamatergic signaling in different cortical states. These findings highlight the significant impact of astrocytes on large-scale neuronal networks, influencing brain activity and responsiveness. Targeting astrocytic signaling pathways shows promise for treating sleep disorders and arousal dysregulation. More research is needed to understand astrocytic calcium signaling in different brain regions and its implications for dysregulated brain states, requiring future human studies to comprehensively investigate neuron-astrocyte interactions and pave the way for therapeutic interventions in sleep- and arousal-related disorders. Related Articles | Metrics

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Ferroptosis: a potential therapeutic target for stroke Chengli Liu#, Guijun Wang, Wenrui Han, Qi Tian, Mingchang Li 2024, 19 (5):  988-997.  doi: 10.4103/1673-5374.385284 Abstract ( 320 )   PDF (2190KB) ( 186 )   Save Ferroptosis is a form of regulated cell death characterized by massive iron accumulation and iron-dependent lipid peroxidation, differing from apoptosis, necroptosis, and autophagy in several aspects. Ferroptosis is regarded as a critical mechanism of a series of pathophysiological reactions after stroke because of iron overload caused by hemoglobin degradation and iron metabolism imbalance. In this review, we discuss ferroptosis-related metabolisms, important molecules directly or indirectly targeting iron metabolism and lipid peroxidation, and transcriptional regulation of ferroptosis, revealing the role of ferroptosis in the progression of stroke. We present updated progress in the intervention of ferroptosis as therapeutic strategies for stroke in vivo and in vitro and summarize the effects of ferroptosis inhibitors on stroke. Our review facilitates further understanding of ferroptosis pathogenesis in stroke, proposes new targets for the treatment of stroke, and suggests that more efforts should be made to investigate the mechanism of ferroptosis in stroke. Related Articles | Metrics

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Mitophagy in neurodegenerative disease pathogenesis Kan Yang, Yuqing Yan, Anni Yu, Ru Zhang, Yuefang Zhang, Zilong Qiu, Zhengyi Li, Qianlong Zhang, Shihao Wu, Fei Li 2024, 19 (5):  998-1005.  doi: 10.4103/1673-5374.385281 Abstract ( 437 )   PDF (2470KB) ( 955 )   Save Mitochondria are critical cellular energy resources and are central to the life of the neuron. Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and homeostasis. Mature neurons are postmitotic and consume substantial energy, thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional mitochondria. Recent evidence indicates that mitophagy is pivotal to the pathogenesis of neurological diseases. However, more work is needed to study mitophagy pathway components as potential therapeutic targets. In this review, we briefly discuss the characteristics of nonselective autophagy and selective autophagy, including ERphagy, aggrephagy, and mitophagy. We then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological conditions. Next, we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate mitophagy. Importantly, we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Last, we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative diseases. Together, our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis. Related Articles | Metrics

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NRF2 signaling cascade in amyotrophic lateral sclerosis: bridging the gap between promise and reality Pauline Tarot, Christelle Lasbleiz, Jean-Charles Liévens 2024, 19 (5):  1006-1012.  doi: 10.4103/1673-5374.385283 Abstract ( 141 )   PDF (4382KB) ( 89 )   Save Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons. Symptoms include muscle weakness and atrophy, spasticity, and progressive paralysis. Currently, there is no treatment to reverse damage to motor neurons and cure amyotrophic lateral sclerosis. The only two treatments actually approved, riluzole and edaravone, have shown mitigated beneficial effects. The difficulty to find a cure lies in the complexity and multifaceted pattern of amyotrophic lateral sclerosis pathogenesis. Among mechanisms, abnormal RNA metabolism, nucleocytoplasmic transport defects, accumulation of unfolded protein, and mitochondrial dysfunction would in fine induce oxidative damage and vice versa. A potent therapeutic strategy will be to find molecules that break this vicious circle. Sharpening the nuclear factor erythroid-2 related factor 2 signaling may fulfill this objective since nuclear factor erythroid-2 related factor 2 has a multitarget profile controlling antioxidant defense, mitochondrial functioning, and inflammation. We here discuss the interest of developing nuclear factor erythroid-2 related factor 2-based therapy in regard to the pathophysiological mechanisms and we provide a general overview of the attempted clinical assays in amyotrophic lateral sclerosis. Related Articles | Metrics

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Progress in the generation of spinal cord organoids over the past decade and future perspectives Gang Zhou, Siyuan Pang, Yongning Li, Jun Gao 2024, 19 (5):  1013-1019.  doi: 10.4103/1673-5374.385280 Abstract ( 363 )   PDF (3190KB) ( 190 )   Save Spinal cord organoids are three-dimensional tissues derived from stem cells that recapitulate the primary morphological and functional characteristics of the spinal cord in vivo. As emerging bioengineering methods have led to the optimization of cell culture protocols, spinal cord organoids technology has made remarkable advancements in the past decade. Our literature search found that current spinal cord organoids do not only dynamically simulate neural tube formation but also exhibit diverse cytoarchitecture along the dorsal-ventral and rostral-caudal axes. Moreover, fused organoids that integrate motor neurons and other regionally specific organoids exhibit intricate neural circuits that allows for functional assessment. These qualities make spinal cord organoids valuable tools for disease modeling, drug screening, and tissue regeneration. By utilizing this emergent technology, researchers have made significant progress in investigating the pathogenesis and potential therapeutic targets of spinal cord diseases. However, at present, spinal cord organoid technology remains in its infancy and has not been widely applied in translational medicine. Establishment of the next generation of spinal cord organoids will depend on good manufacturing practice standards and needs to focus on diverse cell phenotypes and electrophysiological functionality evaluation.  Related Articles | Metrics

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New insights into the therapeutic approaches for the treatment of tauopathies Himanshi Singh, Asmita Das, Mohammad Moshahid Khan, Tayebeh Pourmotabbed 2024, 19 (5):  1020-1026.  doi: 10.4103/1673-5374.385288 Abstract ( 99 )   PDF (1532KB) ( 111 )   Save Tauopathies are a group of neurological disorders, including Alzheimer’s disease and frontotemporal dementia, which involve progressive neurodegeneration, cognitive deficits, and aberrant tau protein accumulation. The development of tauopathies cannot currently be stopped or slowed down by treatment measures. Given the significant contribution of tau burden in primary tauopathies and the strong association between pathogenic tau accumulation and cognitive deficits, there has been a lot of interest in creating therapies that can alleviate tau pathology and render neuroprotective effects. Recently, small molecules, immunotherapies, and gene therapy have been used to reduce the pathological tau burden and prevent neurodegeneration in animal models of tauopathies. However, the major pitfall of the current therapeutic approach is the difficulty of drugs and gene-targeting modalities to cross the blood-brain barrier and their unintended side effects. In this review, the current therapeutic strategies used for tauopathies including the use of oligonucleotide-based gene therapy approaches that have shown a promising result for the treatment of tauopathies and Alzheimer’s disease in preclinical animal models, have been discussed. Related Articles | Metrics

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Antisense therapy: a potential breakthrough in the treatment of neurodegenerative diseases Roberta Romano, Cecilia Bucci 2024, 19 (5):  1027-1035.  doi: 10.4103/1673-5374.385285 Abstract ( 115 )   PDF (2719KB) ( 77 )   Save Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system. Currently, there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide. Therefore, it is necessary to find new therapeutic approaches, and antisense therapies offer this possibility, having the great advantage of not modifying cellular genome and potentially being safer. Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases. The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases, with a focus on those antisense therapies that have already received the approval of the U.S. Food and Drug Administration. Related Articles | Metrics

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Pathological mechanisms of amyotrophic lateral sclerosis Yushu Hu, Wenzhi Chen, Caihui Wei, Shishi Jiang, Shu Li, Xinxin Wang, Renshi Xu 2024, 19 (5):  1036-1044.  doi: 10.4103/1673-5374.382985 Abstract ( 255 )   PDF (1419KB) ( 232 )   Save Amyotrophic lateral sclerosis refers to a neurodegenerative disease involving the motor system, the cause of which remains unexplained despite several years of research. Thus, the journey to understanding or treating amyotrophic lateral sclerosis is still a long one. According to current research, amyotrophic lateral sclerosis is likely not due to a single factor but rather to a combination of mechanisms mediated by complex interactions between molecular and genetic pathways. The progression of the disease involves multiple cellular processes and the interaction between different complex mechanisms makes it difficult to identify the causative factors of amyotrophic lateral sclerosis. Here, we review the most common amyotrophic lateral sclerosis-associated pathogenic genes and the pathways involved in amyotrophic lateral sclerosis, as well as summarize currently proposed potential mechanisms responsible for amyotrophic lateral sclerosis disease and their evidence for involvement in amyotrophic lateral sclerosis. In addition, we discuss current emerging strategies for the treatment of amyotrophic lateral sclerosis. Studying the emergence of these new therapies may help to further our understanding of the pathogenic mechanisms of the disease. Related Articles | Metrics

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Promising use of metformin in treating neurological disorders: biomarker-guided therapies Allison Loan, Charvi Syal, Margarita Lui, Ling He, Jing Wang 2024, 19 (5):  1045-1055.  doi: 10.4103/1673-5374.385286 Abstract ( 115 )   PDF (2033KB) ( 110 )   Save Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases (Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, Huntington’s disease), cerebrovascular conditions (stroke), and neurodevelopmental disorders (autism spectrum disorder). Although they affect millions of individuals around the world, only a limited number of effective treatment options are available today. Since most neurological disorders express mitochondria-related metabolic perturbations, metformin, a biguanide type II antidiabetic drug, has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism. However, controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders. Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging, lifestyle, genetics, and environment, it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders. These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment, ultimately developing targeted therapy. In this review, we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders. Related Articles | Metrics

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Satellite glial cells in sensory ganglia play a wider role in chronic pain via multiple mechanisms Xiaoyun Qiu, Yuanzhi Yang, Xiaoli Da, Yi Wang, Zhong Chen, Cenglin Xu 2024, 19 (5):  1056-1063.  doi: 10.4103/1673-5374.382986 Abstract ( 190 )   PDF (1131KB) ( 173 )   Save Satellite glial cells are unique glial cells that surround the cell body of primary sensory neurons. An increasing body of evidence suggests that in the presence of inflammation and nerve damage, a significant number of satellite glial cells become activated, thus triggering a series of functional changes. This suggests that satellite glial cells are closely related to the occurrence of chronic pain. In this review, we first summarize the morphological structure, molecular markers, and physiological functions of satellite glial cells. Then, we clarify the multiple key roles of satellite glial cells in chronic pain, including gap junction hemichannel Cx43, membrane channel Pannexin1, K channel subunit 4.1, ATP, purinergic P2 receptors, and a series of additional factors and their receptors, including tumor necrosis factor, glutamate, endothelin, and bradykinin. Finally, we propose that future research should focus on the specific sorting of satellite glial cells, and identify genomic differences between physiological and pathological conditions. This review provides an important perspective for clarifying mechanisms underlying the peripheral regulation of chronic pain and will facilitate the formulation of new treatment plans for chronic pain. Related Articles | Metrics

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Tumor necrosis factor-stimulated gene-6 ameliorates early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome-mediated astrocyte pyroptosis Mingxiang Ding, Lei Jin, Boyang Wei, Wenping Cheng, Wenchao Liu, Xifeng Li, Chuanzhi Duan 2024, 19 (5):  1064-1071.  doi: 10.4103/1673-5374.385311 Abstract ( 156 )   PDF (18209KB) ( 57 )   Save Subarachnoid hemorrhage is associated with high morbidity and mortality and lacks effective treatment. Pyroptosis is a crucial mechanism underlying early brain injury after subarachnoid hemorrhage. Previous studies have confirmed that tumor necrosis factor-stimulated gene-6 (TSG-6) can exert a neuroprotective effect by suppressing oxidative stress and apoptosis. However, no study to date has explored whether TSG-6 can alleviate pyroptosis in early brain injury after subarachnoid hemorrhage. In this study, a C57BL/6J mouse model of subarachnoid hemorrhage was established using the endovascular perforation method. Our results indicated that TSG-6 expression was predominantly detected in astrocytes, along with NLRC4 and gasdermin-D (GSDMD). The expression of NLRC4, GSDMD and its N-terminal domain (GSDMD-N), and cleaved caspase-1 was significantly enhanced after subarachnoid hemorrhage and accompanied by brain edema and neurological impairment. To explore how TSG-6 affects pyroptosis during early brain injury after subarachnoid hemorrhage, recombinant human TSG-6 or a siRNA targeting TSG-6 was injected into the cerebral ventricles. Exogenous TSG-6 administration downregulated the expression of NLRC4 and pyroptosis-associated proteins and alleviated brain edema and neurological deficits. Moreover, TSG-6 knockdown further increased the expression of NLRC4, which was accompanied by more severe astrocyte pyroptosis. In summary, our study revealed that TSG-6 provides neuroprotection against early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome activation-induced astrocyte pyroptosis. Related Articles | Metrics

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ATAT1 deficiency enhances microglia/macrophage-mediated erythrophagocytosis and hematoma absorption following intracerebral hemorrhage Yihua Zhang, Ping Huang, Min Cao, Yi Chen, Xinhu Zhao, Xuzhi He, Lunshan Xu 2024, 19 (5):  1072-1077.  doi: 10.4103/1673-5374.382984 Abstract ( 148 )   PDF (2391KB) ( 107 )   Save MIcroglia/macrophage-mediated erythrophagocytosis plays a crucial role in hematoma clearance after intracerebral hemorrhage. Dynamic cytoskeletal changes accompany phagocytosis. However, whether and how these changes are associated with microglia/macrophage-mediated erythrophagocytosis remain unclear. In this study, we investigated the function of acetylated α-tubulin, a stabilized microtubule form, in microglia/macrophage erythrophagocytosis after intracerebral hemorrhage both in vitro and in vivo. We first assessed the function of acetylated α-tubulin in erythrophagocytosis using primary DiO GFP-labeled red blood cells co-cultured with the BV2 microglia or RAW264.7 macrophage cell lines. Acetylated α-tubulin expression was significantly decreased in BV2 and RAW264.7 cells during erythrophagocytosis. Moreover, silencing α-tubulin acetyltransferase 1 (ATAT1), a newly discovered α-tubulin acetyltransferase, decreased Ac-α-tub levels and enhanced the erythrophagocytosis by BV2 and RAW264.7 cells. Consistent with these findings, in ATAT1–/– mice, we observed increased ionized calcium binding adapter molecule 1 (Iba1) and Perls-positive microglia/macrophage phagocytes of red blood cells in peri-hematoma and reduced hematoma volume in mice with intracerebral hemorrhage. Additionally, knocking out ATAT1 alleviated neuronal apoptosis and pro-inflammatory cytokines and increased anti-inflammatory cytokines around the hematoma, ultimately improving neurological recovery of mice after intracerebral hemorrhage. These findings suggest that ATAT1 deficiency accelerates erythrophagocytosis by microglia/macrophages and hematoma absorption after intracerebral hemorrhage. These results provide novel insights into the mechanisms of hematoma clearance and suggest ATAT1 as a potential target for the treatment of intracerebral hemorrhage. Related Articles | Metrics

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P7C3-A20 treats traumatic brain injury in rats by inhibiting excessive autophagy and apoptosis Zhiqing Yang, Zhenchao Wang, Xiaoqi Deng, Lingxin Zhu, Zhaomeng Song, Changyu Cao, Xinran Li 2024, 19 (5):  1078-1083.  doi: 10.4103/1673-5374.380910 Abstract ( 192 )   PDF (5311KB) ( 76 )   Save Traumatic brain injury is a severe health problem leading to autophagy and apoptosis in the brain. 3,6-Dibromo-beta-fluoro-N-(3-methoxyphenyl)-9H-carbazole-9-propanamine (P7C3-A20) can be neuroprotective in various diseases, including ischemic stroke and neurodegenerative diseases. However, whether P7C3-A20 has a therapeutic effect on traumatic brain injury and its possible molecular mechanisms are unclear. Therefore, in the present study, we investigated the therapeutic effects of P7C3-A20 on traumatic brain injury and explored the putative underlying molecular mechanisms. We established a traumatic brain injury rat model using a modified weight drop method. P7C3-A20 or vehicle was injected intraperitoneally after traumatic brain injury. Severe neurological deficits were found in rats after traumatic brain injury, with deterioration in balance, walking function, and learning memory. Furthermore, hematoxylin and eosin staining showed significant neuronal cell damage, while terminal deoxynucleotidyl transferase mediated dUTP nick end labeling staining indicated a high rate of apoptosis. The presence of autolysosomes was observed using transmission electron microscope. P7C3-A20 treatment reversed these pathological features. Western blotting showed that P7C3-A20 treatment reduced microtubule-associated protein 1 light chain 3-II (LC3-II) autophagy protein, apoptosis-related proteins (namely, Bcl-2/adenovirus E1B 19-kDa-interacting protein 3 [BNIP3], and Bcl-2 associated x protein [Bax]), and elevated ubiquitin-binding protein p62 (p62) autophagy protein expression. Thus, P7C3-A20 can treat traumatic brain injury in rats by inhibiting excessive autophagy and apoptosis. Related Articles | Metrics

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The miR-9-5p/CXCL11 pathway is a key target of hydrogen sulfide-mediated inhibition of neuroinflammation in hypoxic ischemic brain injury  Yijing Zhao, Tong Li, Zige Jiang, Chengcheng Gai, Shuwen Yu, Danqing Xin, Tingting Li, Dexiang Liu, Zhen Wang 2024, 19 (5):  1084-1091.  doi: 10.4103/1673-5374.382860 Abstract ( 123 )   PDF (51515KB) ( 62 )   Save We previously showed that hydrogen sulfide (H2S) has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice. However, the precise mechanism underlying the role of H2S in this situation remains unclear. In this study, we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine, a H2S precursor, attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionine β synthase (a major H2S synthetase in the brain) in the prefrontal cortex. We also found that an miR-9-5p inhibitor blocked the expression of cystathionine β synthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia. Furthermore, miR-9-5p overexpression increased cystathionine-β-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury. L-cysteine decreased the expression of CXCL11, an miR-9-5p target gene, in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3, FSTL1, SOCS2 and SOCS5, while treatment with an miR-9-5p inhibitor reversed these changes. These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoring β-synthase expression, thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.   Related Articles | Metrics

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Endorepellin downregulation promotes angiogenesis after experimental traumatic brain injury Qian Zhang, Yao Jing, Qiuyuan Gong, Lin Cai, Ren Wang, Dianxu Yang, Liping Wang, Meijie Qu, Hao Chen, Yaohui Tang, Hengli Tian, Jun Ding, Zhiming Xu 2024, 19 (5):  1092-1097.  doi: 10.4103/1673-5374.382861 Abstract ( 74 )   PDF (3074KB) ( 88 )   Save Endorepellin plays a key role in the regulation of angiogenesis, but its effects on angiogenesis after traumatic brain injury are unclear. This study explored the effects of endorepellin on angiogenesis and neurobehavioral outcomes after traumatic brain injury in mice. Mice were randomly divided into four groups: sham, controlled cortical impact only, adeno-associated virus (AAV)-green fluorescent protein, and AAV-shEndorepellin-green fluorescent protein groups. In the controlled cortical impact model, the transduction of AAV-shEndorepellin-green fluorescent protein downregulated endorepellin while increasing the number of CD31+/Ki-67+ proliferating endothelial cells and the functional microvessel density in mouse brain. These changes resulted in improved neurological function compared with controlled cortical impact mice. Western blotting revealed increased expression of vascular endothelial growth factor and angiopoietin-1 in mice treated with AAV-shEndorepellin-green fluorescent protein. Synchrotron radiation angiography showed that endorepellin downregulation promoted angiogenesis and increased cortical neovascularization, which may further improve neurobehavioral outcomes. Furthermore, an in vitro study showed that downregulation of endorepellin increased tube formation by human umbilical vein endothelial cells compared with a control. Mechanistic analysis found that endorepellin downregulation may mediate angiogenesis by activating vascular endothelial growth factor- and angiopoietin-1-related signaling pathways. Related Articles | Metrics

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Cortical activity in patients with high-functioning ischemic stroke during the Purdue Pegboard Test: insights into bimanual coordinated fine motor skills with functional near-infrared spectroscopy Siyun Chen, Mengchai Mao, Guangyue Zhu, Yufeng Chen, Yuqi Qiu, Bin Ye, Dongsheng Xu 2024, 19 (5):  1098-1104.  doi: 10.4103/1673-5374.385312 Abstract ( 158 )   PDF (10715KB) ( 100 )   Save After stroke, even high-functioning individuals may experience compromised bimanual coordination and fine motor dexterity, leading to reduced functional independence. Bilateral arm training has been proposed as a promising intervention to address these deficits. However, the neural basis of the impairment of functional fine motor skills and their relationship to bimanual coordination performance in stroke patients remains unclear, limiting the development of more targeted interventions. To address this gap, our study employed functional near-infrared spectroscopy to investigate cortical responses in patients after stroke as they perform functional tasks that engage fine motor control and coordination. Twenty-four high-functioning patients with ischemic stroke (7 women, 17 men; mean age 64.75 ± 10.84 years) participated in this cross-sectional observational study and completed four subtasks from the Purdue Pegboard Test, which measures unimanual and bimanual finger and hand dexterity. We found significant bilateral activation of the sensorimotor cortices during all Purdue Pegboard Test subtasks, with bimanual tasks inducing higher cortical activation than the assembly subtask. Importantly, patients with better bimanual coordination exhibited lower cortical activation during the other three Purdue Pegboard Test subtasks. Notably, the observed neural response patterns varied depending on the specific subtask. In the unaffected hand task, the differences were primarily observed in the ipsilesional hemisphere. In contrast, the bilateral sensorimotor cortices and the contralesional hemisphere played a more prominent role in the bimanual task and assembly task, respectively. While significant correlations were found between cortical activation and unimanual tasks, no significant correlations were observed with bimanual tasks. This study provides insights into the neural basis of bimanual coordination and fine motor skills in high-functioning patients after stroke, highlighting task-dependent neural responses. The findings also suggest that patients who exhibit better bimanual performance demonstrate more efficient cortical activation. Therefore, incorporating bilateral arm training in post-stroke rehabilitation is important for better outcomes. The combination of functional near-infrared spectroscopy with functional motor paradigms is valuable for assessing skills and developing targeted interventions in stroke rehabilitation. Related Articles | Metrics

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Conditioned medium from human dental pulp stem cells treats spinal cord injury by inhibiting microglial pyroptosis Tao Liu, Ziqian Ma, Liang Liu, Yilun Pei, Qichao Wu, Songjie Xu, Yadong Liu, Nan Ding, Yun Guan, Yan Zhang, Xueming Chen 2024, 19 (5):  1105-1111.  doi: 10.4103/1673-5374.385309 Abstract ( 121 )   PDF (7010KB) ( 53 )   Save Human dental pulp stem cell transplantation has been shown to be an effective therapeutic strategy for spinal cord injury. However, whether the human dental pulp stem cell secretome can contribute to functional recovery after spinal cord injury remains unclear. In the present study, we established a rat model of spinal cord injury based on impact injury from a dropped weight and then intraperitoneally injected the rats with conditioned medium from human dental pulp stem cells. We found that the conditioned medium effectively promoted the recovery of sensory and motor functions in rats with spinal cord injury, decreased expression of the microglial pyroptosis markers NLRP3, GSDMD, caspase-1, and interleukin-1β, promoted axonal and myelin regeneration, and inhibited the formation of glial scars. In addition, in a lipopolysaccharide-induced BV2 microglia model, conditioned medium from human dental pulp stem cells protected cells from pyroptosis by inhibiting the NLRP3/caspase-1/interleukin-1β pathway. These results indicate that conditioned medium from human dental pulp stem cells can reduce microglial pyroptosis by inhibiting the NLRP3/caspase-1/interleukin-1β pathway, thereby promoting the recovery of neurological function after spinal cord injury. Therefore, conditioned medium from human dental pulp stem cells may become an alternative therapy for spinal cord injury. Related Articles | Metrics

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Casein kinase-2 inhibition promotes retinal ganglion cell survival after acute intraocular pressure elevation Meng Wang, Shi-Qi Yao, Yao Huang, Jia-Jian Liang, Yanxuan Xu, Shaowan Chen, Yuhang Wang, Tsz Kin Ng, Wai Kit Chu, Qi Cui, Ling-Ping Cen 2024, 19 (5):  1112-1118.  doi: 10.4103/1673-5374.385310 Abstract ( 94 )   PDF (10848KB) ( 26 )   Save Intraocular pressure elevation can induce retinal ganglion cell death and is a clinically reversible risk factor for glaucoma, the leading cause of irreversible blindness. We previously demonstrated that casein kinase-2 inhibition can promote retinal ganglion cell survival and axonal regeneration in rats after optic nerve injury. To investigate the underlying mechanism, in the current study we increased the intraocular pressure of adult rats to 75 mmHg for 2 hours and then administered a casein kinase-2 inhibitor (4,5,6,7-tetrabromo-2-azabenzimidazole or 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole) by intravitreal injection. We found that intravitreal injection of 4,5,6,7-tetrabromo-2-azabenzimidazole or 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole promoted retinal ganglion cell survival and reduced the number of infiltrating macrophages. Transcriptomic analysis showed that the mitogen activated protein kinase signaling pathway was involved in the response to intraocular pressure elevation but was not modulated by the casein kinase-2 inhibitors. Furthermore, casein kinase-2 inhibition downregulated the expression of genes (Cck, Htrsa, Nef1, Htrlb, Prph, Chat, Slc18a3, Slc5a7, Scn1b, Crybb2, Tsga10ip, and Vstm21) involved in intraocular pressure elevation. Our data indicate that inhibition of casein kinase-2 can enhance retinal ganglion cell survival in rats after acute intraocular pressure elevation via macrophage inactivation.  Related Articles | Metrics

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Translocation of telomerase reverse transcriptase coincided with ATP release in postnatal cochlear supporting cells Yukai Zhang, Keyong Tian, Wei Wei, Wenjuan Mi, Fei Lu, Zhenzhen Liu, Qingwen Zhu, Xinyu Zhang, Panling Geng, Jianhua Qiu, Yongli Song, Dingjun Zha 2024, 19 (5):  1119-1125.  doi: 10.4103/1673-5374.382862 Abstract ( 106 )   PDF (7237KB) ( 33 )   Save The spontaneous bursts of electrical activity in the developing auditory system are derived from the periodic release of adenosine triphosphate (ATP) by supporting cells in the Kölliker’s organ. However, the mechanisms responsible for initiating spontaneous ATP release have not been determined. Our previous study revealed that telomerase reverse transcriptase (TERT) is expressed in the basilar membrane during the first postnatal week. Its role in cochlear development remains unclear. In this study, we investigated the expression and role of TERT in postnatal cochlea supporting cells. Our results revealed that in postnatal cochlear Kölliker’s organ supporting cells, TERT shifts from the nucleus into the cytoplasm over time. We found that the TERT translocation tendency in postnatal cochlear supporting cells in vitro coincided with that observed in vivo. Further analysis showed that TERT in the cytoplasm was mainly located in mitochondria in the absence of oxidative stress or apoptosis, suggesting that TERT in mitochondria plays roles other than antioxidant or anti-apoptotic functions. We observed increased ATP synthesis, release and activation of purine signaling systems in supporting cells during the first 10 postnatal days. The phenomenon that TERT translocation coincided with changes in ATP synthesis, release and activation of the purine signaling system in postnatal cochlear supporting cells suggested that TERT may be involved in regulating ATP release and activation of the purine signaling system. Our study provides a new research direction for exploring the spontaneous electrical activity of the cochlea during the early postnatal period. Related Articles | Metrics

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Epidemiological and clinical features, treatment status, and economic burden of traumatic spinal cord injury in China: a hospital-based retrospective study Hengxing Zhou, Yongfu Lou, Lingxiao Chen, Yi Kang, Lu Liu, Zhiwei Cai, David B. Anderson, Wei Wang, Chi Zhang, Jinghua Wang, Guangzhi Ning, Yanzheng Gao, Baorong He, Wenyuan Ding, Yisheng Wang, Wei Mei, Yueming Song, Yue Zhou, Maosheng Xia, Huan Wang, Jie Zhao, Guoyong Yin, Tao Zhang, Feng Jing, Rusen Zhu, Bin Meng, Li Duan, Zhongmin Zhang, Desheng Wu, Zhengdong Cai, Lin Huang, Zhanhai Yin, Kainan Li, Shibao Lu, Shiqing Feng 2024, 19 (5):  1126-1132.  Abstract ( 343 )   PDF (1711KB) ( 212 )   Save Traumatic spinal cord injury is potentially catastrophic and can lead to permanent disability or even death. China has the largest population of patients with traumatic spinal cord injury. Previous studies of traumatic spinal cord injury in China have mostly been regional in scope; national-level studies have been rare. To the best of our knowledge, no national-level study of treatment status and economic burden has been performed. This retrospective study aimed to examine the epidemiological and clinical features, treatment status, and economic burden of traumatic spinal cord injury in China at the national level. We included 13,465 traumatic spinal cord injury patients who were injured between January 2013 and December 2018 and treated in 30 hospitals in 11 provinces/municipalities representing all geographical divisions of China. Patient epidemiological and clinical features, treatment status, and total and daily costs were recorded. Trends in the percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department and cost of care were assessed by annual percentage change using the Joinpoint Regression Program. The percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department did not significantly change overall (annual percentage change, –0.5% and 2.1%, respectively). A total of 10,053 (74.7%) patients underwent surgery. Only 2.8% of patients who underwent surgery did so within 24 hours of injury. A total of 2005 (14.9%) patients were treated with high-dose (≥ 500 mg) methylprednisolone sodium succinate/methylprednisolone (MPSS/MP); 615 (4.6%) received it within 8 hours. The total cost for acute traumatic spinal cord injury decreased over the study period (–4.7%), while daily cost did not significantly change (1.0% increase). Our findings indicate that public health initiatives should aim at improving hospitals’ ability to complete early surgery within 24 hours, which is associated with improved sensorimotor recovery, increasing the awareness rate of clinical guidelines related to high-dose MPSS/MP to reduce the use of the treatment with insufficient evidence.   Related Articles | Metrics

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Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory  Baicheng Zhao, Hang Zhang, Ying Liu, Gaoyu Zu, Yuxiao Zhang, Jiayi Hu, Shuai Liu, Linya You 2024, 19 (5):  1133-1141.  doi: 10.4103/1673-5374.385307 Abstract ( 140 )   PDF (3674KB) ( 132 )   Save Bromodomain and plant homeodomain (PHD) finger containing protein 1 (Brpf1) is an activator and scaffold protein of a multiunit complex that includes other components involving lysine acetyltransferase (KAT) 6A/6B/7. Brpf1, KAT6A, and KAT6B mutations were identified as the causal genes of neurodevelopmental disorders leading to intellectual disability. Our previous work revealed strong and specific expression of Brpf1 in both the postnatal and adult forebrain, especially the hippocampus, which has essential roles in learning and memory. Here, we hypothesized that Brpf1 plays critical roles in the function of forebrain excitatory neurons, and that its deficiency leads to learning and memory deficits. To test this, we knocked out Brpf1 in forebrain excitatory neurons using CaMKIIa-Cre. We found that Brpf1 deficiency reduced the frequency of miniature excitatory postsynaptic currents and downregulated the expression of genes Pcdhgb1, Slc16a7, Robo3, and Rho, which are related to neural development, synapse function, and memory, thereby damaging spatial and fear memory in mice. These findings help explain the mechanisms of intellectual impairment in patients with BRPF1 mutation. Related Articles | Metrics

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Bromocriptine protects perilesional spinal cord neurons from lipotoxicity after spinal cord injury Ying Peng, Zhuoxuan Li, Zhiyang Zhang, Yinglun Chen, Renyuan Wang, Nixi Xu, Yuanwu Cao, Chang Jiang, Zixian Chen, Haodong Lin 2024, 19 (5):  1142-1149.  doi: 10.4103/1673-5374.385308 Abstract ( 137 )   PDF (36401KB) ( 65 )   Save Recent studies have revealed that lipid droplets accumulate in neurons after brain injury and evoke lipotoxicity, damaging the neurons. However, how lipids are metabolized by spinal cord neurons after spinal cord injury remains unclear. Herein, we investigated lipid metabolism by spinal cord neurons after spinal cord injury and identified lipid-lowering compounds to treat spinal cord injury. We found that lipid droplets accumulated in perilesional spinal cord neurons after spinal cord injury in mice. Lipid droplet accumulation could be induced by myelin debris in HT22 cells. Myelin debris degradation by phospholipase led to massive free fatty acid production, which increased lipid droplet synthesis, β-oxidation, and oxidative phosphorylation. Excessive oxidative phosphorylation increased reactive oxygen species generation, which led to increased lipid peroxidation and HT22 cell apoptosis. Bromocriptine was identified as a lipid-lowering compound that inhibited phosphorylation of cytosolic phospholipase A2 by reducing the phosphorylation of extracellular signal-regulated kinases 1/2 in the mitogen-activated protein kinase pathway, thereby inhibiting myelin debris degradation by cytosolic phospholipase A2 and alleviating lipid droplet accumulation in myelin debris-treated HT22 cells. Motor function, lipid droplet accumulation in spinal cord neurons and neuronal survival were all improved in bromocriptine-treated mice after spinal cord injury. The results suggest that bromocriptine can protect neurons from lipotoxic damage after spinal cord injury via the extracellular signal-regulated kinases 1/2-cytosolic phospholipase A2 pathway. Related Articles | Metrics

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The autophagy protein Atg9 functions in glia and contributes to parkinsonian symptoms in a Drosophila model of Parkinson’s disease Shuanglong Yi, Linfang Wang, Margaret S. Ho, Shiping Zhang 2024, 19 (5):  1150-1155.  doi: 10.4103/1673-5374.382259 Abstract ( 195 )   PDF (3525KB) ( 71 )   Save Parkinson’s disease is a progressive neurodegenerative disease characterized by motor deficits, dopaminergic neuron loss, and brain accumulation of α-synuclein aggregates called Lewy bodies. Dysfunction in protein degradation pathways, such as autophagy, has been demonstrated in neurons as a critical mechanism for eliminating protein aggregates in Parkinson’s disease. However, it is less well understood how protein aggregates are eliminated in glia, the other cell type in the brain. In the present study, we show that autophagy-related gene 9 (Atg9), the only transmembrane protein in the autophagy machinery, is highly expressed in Drosophila glia from adult brain. Results from immunostaining and live cell imaging analysis reveal that a portion of Atg9 localizes to the trans-Golgi network, autophagosomes, and lysosomes in glia. Atg9 is persistently in contact with these organelles. Lacking glial atg9 reduces the number of omegasomes and autophagosomes, and impairs autophagic substrate degradation. This suggests that glial Atg9 participates in the early steps of autophagy, and hence the control of autophagic degradation. Importantly, loss of glial atg9 induces parkinsonian symptoms in Drosophila including progressive loss of dopaminergic neurons, locomotion deficits, and glial activation. Our findings identify a functional role of Atg9 in glial autophagy and establish a potential link between glial autophagy and Parkinson’s disease. These results may provide new insights on the underlying mechanism of Parkinson’s disease. Related Articles | Metrics

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Increased retinal venule diameter as a prognostic indicator for recurrent cerebrovascular events: a prospective observational study#br# Ying Zhao, Dawei Dong, Ding Yan, Bing Yang, Weirong Gui, Man Ke, Anding Xu, Zefeng Tan 2024, 19 (5):  1156-1160.  doi: 10.4103/1673-5374.382863 Abstract ( 95 )   PDF (1179KB) ( 39 )   Save Microvasculature of the retina is considered an alternative marker of cerebral vascular risk in healthy populations. However, the ability of retinal vasculature changes, specifically focusing on retinal vessel diameter, to predict the recurrence of cerebrovascular events in patients with ischemic stroke has not been determined comprehensively. While previous studies have shown a link between retinal vessel diameter and recurrent cerebrovascular events, they have not incorporated this information into a predictive model. Therefore, this study aimed to investigate the relationship between retinal vessel diameter and subsequent cerebrovascular events in patients with acute ischemic stroke. Additionally, we sought to establish a predictive model by combining retinal veessel diameter with traditional risk factors. We performed a prospective observational study of 141 patients with acute ischemic stroke who were admitted to the First Affiliated Hospital of Jinan University. All of these patients underwent digital retinal imaging within 72 hours of admission and were followed up for 3 years. We found that, after adjusting for related risk factors, patients with acute ischemic stroke with mean arteriolar diameter within 0.5–1.0 disc diameters of the disc margin (MAD0.5–1.0DD) of ≥ 74.14 μm and mean venular diameter within 0.5–1.0 disc diameters of the disc margin (MVD0.5–1.0DD) of ≥ 83.91 μm tended to experience recurrent cerebrovascular events. We established three multivariate Cox proportional hazard regression models: model 1 included traditional risk factors, model 2 added MAD0.5–1.0DD to model 1, and model 3 added MVD0.5–1.0DD to model 1. Model 3 had the greatest potential to predict subsequent cerebrovascular events, followed by model 2, and finally model 1. These findings indicate that combining retinal venular or arteriolar diameter with traditional risk factors could improve the prediction of recurrent cerebrovascular events in patients with acute ischemic stroke, and that retinal imaging could be a useful and non-invasive method for identifying high-risk patients who require closer monitoring and more aggressive management. Related Articles | Metrics