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15 August 2024, Volume 19 Issue 8 Previous Issue   

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New pharmacological tools: the use of diterpenes to promote adult hippocampal neurogenesis Ricardo Gómez-Oliva, Pedro Nunez-Abades, Carmen Castro 2024, 19 (8):  1629-1630.  doi: 10.4103/1673-5374.389635 Abstract ( 80 )   PDF (432KB) ( 62 )   Save Tissue regeneration maintains homeostasis and preserves the functional features of each tissue. However, not all tissues show a strong repairing capacity. This is the case of the central nervous system. It is now well established that the generation of new functional neurons from stem cells in the adult brain occurs in specific regions of the brain of different species such as rodents, birds, primates, and humans (Eriksson et al., 1998). The brain areas in which neurogenesis occurs are referred to as neurogenic niches, regions in which neural stem cells (NSC) are surrounded by cells and signaling molecules that lead their fate toward mature neurons. Two main neurogenic niches have been thoroughly described in adult rodents: the subventricular zone and the dentate gyrus of the hippocampus (DG). NSC in the adult DG remain mainly in a quiescent non-proliferative state (qNSC) and are able to generate neurons through a complex hierarchical process that involves the activation of neural stem cells, the generation of undifferentiated progenitors, and the origination of immature neurons that differentiate into mature functional neurons. Newly generated neurons migrate short distances from the subgranular zone to the granular layer, where through their axons, they integrate into pre-existing circuits by establishing connections with CA3 and CA2 regions. These neurons participate in several tasks that involve the hippocampus such as memory consolidation, spatial and temporal pattern discrimination, or forgetting, among others. Related Articles | Metrics

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Clustering of voltage-gated ion channels as an evolutionary trigger of myelin formation Henrike Ohm, Simone Rey, Christian Klämbt 2024, 19 (8):  1631-1632.  doi: 10.4103/1673-5374.389636 Abstract ( 81 )   PDF (1831KB) ( 42 )   Save Neurons carry apical dendrites that perceive information and a basal axon that transmits the computed information towards its targets. The axon originates at the axon hillock which is followed by the axon initial segment. Here, action potentials are initiated that are based on millisecond long openings of specific voltage-gated sodium and potassium channels that are conserved in all parahoxozoa (Placozoa, Cnidaria, Bilateria) (Li et al., 2015). This indicates that the basic principles in action potential generation and spreading are evolutionarily conserved. The conductance velocity of action potentials likely affects the evolutionary success of any animal species as it contributes, for example, to the success of escape responses. Physical laws state that axonal transduction velocity depends on the size of the axon. Alternatively, conductance speed is gained by arranging voltage-gated ion channels in spatially separated clusters. Such a distribution is thought to be a defining feature of the vertebrate nervous system and accumulations of voltage-gated ion channels are seen at the axon initial segment and the nodes of Ranvier. Together with intervening myelin, this enables saltatory transduction, which allows very fast conduction velocities. Surprisingly, recent work demonstrated a clustered distribution of voltage-gated ion channels in the nervous system of the invertebrate Drosophila melanogaster (Rey et al., 2023). Channels are enriched at the axon initial segments of motor- and sensory neurons, cluster on a molecular scale with spacing of about 0.7 µm, supporting micro-saltatory conductance. Similar to in vertebrates, the positioning of ion channels is influenced by glia. Moreover, glia in adult flies form myelin-like structures next to the axon initial segments (Rey et al., 2023). Thus, the evolution of saltatory conductance is not specific to vertebrates but likely started before the separation of vertebrates and invertebrates. Related Articles | Metrics

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Using microglia-derived extracellular vesicles to capture diversity of microglial activation phenotypes following neurological injury Austyn D. Roseborough, Nikita Ollen-Bittle, Shawn N. Whitehead 2024, 19 (8):  1633-1634.  doi: 10.4103/1673-5374.389632 Abstract ( 70 )   PDF (1159KB) ( 35 )   Save Microglia are one of the three glial cell populations in the central nervous system (CNS), along with astrocytes and oligodendrocytes. While microglia are unique among brain cells due to their hematologic origin and perform immune functions similar to peripheral macrophages, they are not simply macrophages of the CNS. Microglia are crucial for many brain-specific functions such as synaptic pruning, facilitation of myelin turnover and communication with both neurons and astrocytes (Saijo and Glass, 2011). They are a highly active cell type, constantly surveying their environment and responding to both exogenous and endogenous danger signals which can include reactive oxygen species, cytosolic DNA, heat shock proteins, plasma proteins and microbial components. Related Articles | Metrics

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Sexual dimorphism of G protein-coupled receptor signaling in the brain Sara Aljoudi, Hamdan Hamdan, Khaled S. Abd-Elrahman 2024, 19 (8):  1635-1636.  doi: 10.4103/1673-5374.389637 Abstract ( 79 )   PDF (675KB) ( 39 )   Save G protein-coupled receptors (GPCRs) represent the most substantial family of membrane receptors that are targeted by U.S. Food and Drug Administration-approved drugs. Much of the preclinical research to understand the pharmacology of many membrane receptors including GPCRs is derived from studies in male animal models (Karp and Reavey, 2019). This can be of concern as emerging evidence reveals unexpected sex-dependent differences in GPCR pharmacodynamics. Thus, understanding the sex-specific disparities in GPCR pharmacological fingerprints can aid in developing targeted ligands that precisely correct GPCR signaling modalities in men and women and ultimately, enhance their effectiveness for certain pathophysiological conditions. We will attempt to summarize the current evidence supporting the sex-biased signaling of GPCRs implicated in several brain disorders.  Related Articles | Metrics

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Glycolysis and glucose metabolism as a target for bioenergetic and neuronal protection in glaucoma Pete A. Williams, Robert J. Casson 2024, 19 (8):  1637-1638.  doi: 10.4103/1673-5374.389638 Abstract ( 134 )   PDF (492KB) ( 50 )   Save Vision is arguably our most valued sense, yet approximately 340 million people globally suffer blindness or moderate visual impairment, highlighting the need to further develop and advance treatments for ophthalmic diseases. Glaucoma refers to a group of ocular disorders united by a clinically characteristic optic neuropathy with associated retinal ganglion cell loss. It is one of the most prevalent neurodegenerations globally, the leading cause of irreversible blindness, and affects ~80 million people worldwide (with an estimated further 40 million undiagnosed). Related Articles | Metrics

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MAP4K inhibition as a potential therapy for amyotrophic lateral sclerosis Shuaipeng Ma, Chun-Li Zhang 2024, 19 (8):  1639-1640.  doi: 10.4103/1673-5374.389639 Abstract ( 80 )   PDF (868KB) ( 33 )   Save Amyotrophic lateral sclerosis (ALS) is a rare neurological disease, featuring gradual loss of muscle controls due to degeneration of motor neurons. Unfortunately, there is currently no cure for ALS. The available therapies only offer a limited extension of survival by several months, begging for more options of therapeutics.  Related Articles | Metrics

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Role of fullerenols derivative 3HFWC in the treatment of Alzheimer’s disease Sanja Ivkovic, Djuro Koruga 2024, 19 (8):  1641-1642.  doi: 10.4103/1673-5374.389641 Abstract ( 111 )   PDF (653KB) ( 50 )   Save Fullerenes: The extensive development of nanoscience that has marked this century continues to evolve, producing new materials, structures, and devices for the treatments of diverse pathologies. Fullerenes are a family of nanoparticles with great applicative promise due to their small size (approximately 1 nm in diameter), structure, and capacity to cross biological barriers. Fullerene is the third pure crystal carbon form, with carbon atoms forming fused rings containing five to seven atoms that have been accidentally synthesized in 1985. This discovery led to the authors’ Nobel Prize in Chemistry award in 1996, and afterward, fullerenes were detected in nature and outer space. The Fullerene family is named after buckminsterfullerene (C60). This most famous member, in turn, is named as an homage to Buckminster Fuller, an American architect, systems theorist, author, designer, inventor, and futurist (who used similar structural principles for architectural objects he designed). Related Articles | Metrics

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Monomeric C-reactive protein: a link between chronic inflammation and neurodegeneration? Nicoleta Arnaut, Ylenia Pastorello, Mark Slevin 2024, 19 (8):  1643-1644.  doi: 10.4103/1673-5374.389640 Abstract ( 71 )   PDF (953KB) ( 26 )   Save Pre-diabetic insulin resistance is associated with sub-clinical inflammation and concomitant increase in systemic C-reactive protein (CRP) levels. Type 2 diabetes mellitus (T2DM) patients register even higher chronic levels of inflammation, with excess circulating CRP originating from both typical hepatic synthesis, and also visceral white adipose tissue. In addition, infiltration of pro-inflammatory macrophages into the expanding fat, as obesity becomes morbid, contributes further to dysregulation and symptomatic disease (Stanimirovic et al., 2022). Most importantly, in diabetic individuals, a sustained and chronic inflammation is perpetuated in the presence of non-healing wounds and ulcers, with associated further increase in CRP (Dangwal et al., 2015). Related Articles | Metrics

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Alterations of protein homeostasis in Alzheimer’s disease: beyond Procrustean bed of endoplasmic reticulum stress and unfolded protein response Dmitry Lim, Alexei Verkhratsky 2024, 19 (8):  1645-1646.  doi: 10.4103/1673-5374.389642 Abstract ( 80 )   PDF (677KB) ( 63 )   Save Alzheimer’s disease (AD) is a major age-related form of dementia with a number of cases exponentially growing, causing enormous social and economic impact on individuals and society. Neuropathological hallmarks of AD, evident in postmortem AD brains, include a massive loss of the grey matter in the neocortex, extracellular deposition of amyloid-β (Aβ) in the form of senile plaques and cerebrovascular amyloid angiopathy, and intra-neuronal accumulation of neurofibrillary tangles, formed by hyper-phosphorylated tau protein. The (most popular) Aβ cascade hypothesis posits the causal role of the aberrant processing of amyloid precursor protein, leading to the release and accumulation of Aβ. This hypothesis stems (possibly erroneously) from the presumed similarity of sporadic AD to inherited, rare familial AD form, triggered by mutations in amyloid precursor protein itself and presenilins 1 and 2 that form a catalytic core of the amyloid precursor protein processing protease γ-secretase. For a long time Aβ cascade hypothesis guided drug development studies and clinical trials in AD field. However, the failure of clinical trials of potential anti-AD drugs reflects a much higher complexity of AD pathogenesis. The main conceptual achievement of the last three decades in AD research has been the understanding that the cellular and biochemical abnormalities precede, by several decades, the emergence of clinical symptoms, indicating that the onset of AD occurs at the youth/middle age of potential AD patients (Selkoe and Hardy, 2016). This highlights the preclinical and prodromal stages as the major window of opportunity for disease-modifying therapy (Figure 1). Related Articles | Metrics

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The big data challenge – and how polypharmacology supports the translation from pre-clinical research into clinical use against neurodegenerative diseases and beyond Sven Marcel Stefan, Muhammad Rafehi 2024, 19 (8):  1647-1648.  doi: 10.4103/1673-5374.387984 Abstract ( 61 )   PDF (404KB) ( 34 )   Save Introductory comments: The identification and validation of disease-modifying proteins are fundamental aspects in drug development. However, the multifactority of neurodegenerative diseases poses a real challenge for targeted therapies. Furthermore, the behavior of individually (over-)expressed target proteins in vitro is likely to differ from their actual functional behavior when embedded in cascades and pathways in vivo. Increased compartmentalization, e.g., in the brain, adds to the complexity. Related Articles | Metrics

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p38-MAPK and CDK5, signaling pathways in neuroinflammation: a potential therapeutic intervention in Alzheimer’s disease? Vlad Ionut Viorel, Ylenia Pastorello, Nosherwan Bajwa, Mark Slevin 2024, 19 (8):  1649-1650.  doi: 10.4103/1673-5374.389645 Abstract ( 153 )   PDF (437KB) ( 66 )   Save Alzheimer’s disease (AD), the most common type of dementia, affects millions of people worldwide, putting a significant strain on healthcare infrastructure and societal resources. AD is characterized by the build-up of amyloid-beta (Aβ) plaques and neurofibrillary tangles containing hyperphosphorylated tau protein. These pathological features cause neuroinflammation, vascular dysfunction, and ultimately, neuronal death and cognitive decline (Long and Holtzman, 2019). Two critical signaling pathways, the mitogen-activated protein kinase (MAPK) family and cyclin-dependent kinase 5 (CDK5), have been implicated in the pathogenesis of AD. There are three primary subfamilies within the MAPK family, namely extracellular signal-regulated kinases, c-Jun N-terminal kinases, and p38 MAPKs. Of these, p38α MAPK is particularly involved in neuroinflammation and vascular dysfunction, processes that are integral to the progression of AD. CDK5, a serine/threonine kinase primarily expressed in the central nervous system, has crucial roles in neuronal migration, synapse formation, and synaptic plasticity. However, aberrant activation of CDK5 has been linked to various neurodegenerative diseases, including AD. Related Articles | Metrics

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Modifying the progression of Parkinson’s disease through movement interventions: multimodal quantification of underlying mechanisms Manuel Bange, Damian Marc Herz, Dumitru Ciolac, Gabriel Gonzalez-Escamilla, Sergiu Groppa 2024, 19 (8):  1651-1652.  doi: 10.4103/1673-5374.389633 Abstract ( 102 )   PDF (521KB) ( 40 )   Save Introduction: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. The pathological hallmark is the progressive loss of dopaminergic neurons of the substantia nigra pars compacta, which is accompanied by widespread alterations in the structure and function of distributed brain networks. Together, these processes cause a variety of motor symptoms such as bradykinesia, rigidity, tremor, gait disorders, or difficulties in fine motor control (Bange et al., 2022). Related Articles | Metrics

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Targeting muscle to treat Charcot-Marie-Tooth disease David Villarroel-Campos, James N. Sleigh 2024, 19 (8):  1653-1654.  doi: 10.4103/1673-5374.389634 Abstract ( 75 )   PDF (799KB) ( 32 )   Save Charcot-Marie-Tooth disease (CMT) is a hereditary peripheral neuropathy causing muscle weakness/wasting and sensory dysfunction predominantly in limb extremities. CMT patients display gait abnormalities, foot deformities, loss of sensation and decreased/absent deep tendon reflexes, with motor symptoms usually being more prominent than sensory. Resulting from > 1500 different mutations across > 100 diverse genes, CMT affects 1 in ≈2500 people and is inherited in an autosomal recessive, autosomal dominant or X-linked fashion. Based on assessment of nerve conduction velocity, CMT is divided into Type 1/demyelinating CMT, in which perturbed Schwann cell homeostasis affects saltatory conduction and reduces nerve conduction velocity, and Type 2/axonal CMT, where motor and sensory axons are lost without affecting nerve conduction velocity. There are also intermediate forms of CMT that share features of demyelinating and axonal neuropathies, including intermediate nerve conduction velocity values. Related Articles | Metrics

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Suppression of mature TAU isoforms prevents Alzheimer’s disease-like amyloid-beta oligomer-induced spine loss in rodent neurons Sarah Buchholz, Hans Zempel 2024, 19 (8):  1655-1657.  doi: 10.4103/1673-5374.389644 Abstract ( 97 )   PDF (8203KB) ( 32 )   Save Introduction: TAU isoforms as disease mediators: The microtubule-associated protein TAU is predominantly present in the axons of neurons under physiological conditions. In Alzheimer’s disease (AD) and related tauopathies, TAU also mislocalizes (“TAU missorting”) to the soma and the dendrites, where it eventually forms aggregates, the so-called neurofibrillary tangles (for review see Zimmer-Bensch and Zempel, 2021; Zempel, 2023). Alternative splicing of the TAU encoding MAPT gene results in eight major TAU isoforms, six of which are expressed in the human brain, while only three are present in the adult rodent brain (Goedert et al., 1989; Bullmann et al., 2009). The axodendritic distribution of the different TAU isoforms is strikingly different in neurons. The longest and least expressed (< 10% of the whole TAUom in the human central nervous system (CNS)) isoform of TAU, 2N4R-TAU, e.g., is partially retained in the somatodendritic compartment, where it induces enhanced dendritic outgrowth and spine maturation (Zempel et al., 2017; Bachmann et al., 2021). Amyloid-beta oligomers (AβO) induce pathological TAU missorting and the loss of dendritic spines, a sensitive measure of synaptic health and function. Interestingly, TAU depletion in mice, primary rodent neurons, and induced pluripotent stem cell (iPSC)-derived human neurons protects them from AβO toxicity, spine loss, and consequential neuronal dysfunction (Roberson et al., 2007; Zempel et al., 2013; Buchholz et al., 2022). Related Articles | Metrics

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Small molecular decoys in Alzheimer’s disease Sho Oasa, Valentina L. Kouznetsova, Igor F. Tsigelny, Lars Terenius 2024, 19 (8):  1658-1659.  doi: 10.4103/1673-5374.389643 Abstract ( 84 )   PDF (379KB) ( 21 )   Save Recent progress in the treatment of Alzheimer’s disease (AD) using antibodies against amyloid sustains amyloid generation as a key process in AD. Amyloid formation starts with two amyloid-beta (Aβ) molecules interacting (dimer formation) followed by an accelerating build-up of so-called protofibrils, which turn into fibrils, which accumulate in the characteristic plaques. To interfere with the process at the root we used molecular modeling to define the surfaces of interaction in dimer formation. In a series of small molecules, we identified candidates that changed the course of interactions and generated aggregates with other macrostructures and reduced toxicity. We have introduced the term “decoys” to identify these molecules. Related Articles | Metrics

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Crosstalk among mitophagy, pyroptosis, ferroptosis, and necroptosis in central nervous system injuries Li Zhang, Zhigang Hu, Zhenxing Li, Yixing Lin 2024, 19 (8):  1660-1670.  doi: 10.4103/1673-5374.389361 Abstract ( 249 )   PDF (3248KB) ( 200 )   Save Central nervous system injuries have a high rate of resulting in disability and mortality; however, at present, effective treatments are lacking. Programmed cell death, which is a genetically determined form of active and ordered cell death with many types, has recently attracted increasing attention due to its functions in determining the fate of cell survival. A growing number of studies have suggested that programmed cell death is involved in central nervous system injuries and plays an important role in the progression of brain damage. In this review, we provide an overview of the role of programmed cell death in central nervous system injuries, including the pathways involved in mitophagy, pyroptosis, ferroptosis, and necroptosis, and the underlying mechanisms by which mitophagy regulates pyroptosis, ferroptosis, and necroptosis. We also discuss the new direction of therapeutic strategies targeting mitophagy for the treatment of central nervous system injuries, with the aim to determine the connection between programmed cell death and central nervous system injuries and to identify new therapies to modulate programmed cell death following central nervous system injury. In conclusion, based on these properties and effects, interventions targeting programmed cell death could be developed as potential therapeutic agents for central nervous system injury patients. Related Articles | Metrics

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Glucagon-like peptide 1 receptor activation: anti-inflammatory effects in the brain#br# Yolanda Diz-Chaves, Zainab Maastor, Carlos Spuch, José Antonio Lamas, Lucas C. González-Matías, Federico Mallo 2024, 19 (8):  1671-1677.  doi: 10.4103/1673-5374.389626 Abstract ( 99 )   PDF (2263KB) ( 64 )   Save The glucagon-like peptide 1 is a pleiotropic hormone that has potent insulinotropic effects and is key in treating metabolic diseases such as diabetes and obesity. Glucagon-like peptide 1 exerts its effects by activating a membrane receptor identified in many tissues, including different brain regions. Glucagon-like peptide 1 activates several signaling pathways related to neuroprotection, like the support of cell growth/survival, enhancement promotion of synapse formation, autophagy, and inhibition of the secretion of proinflammatory cytokines, microglial activation, and apoptosis during neural morphogenesis. The glial cells, including astrocytes and microglia, maintain metabolic homeostasis and defense against pathogens in the central nervous system. After brain insult, microglia are the first cells to respond, followed by reactive astrocytosis. These activated cells produce proinflammatory mediators like cytokines or chemokines to react to the insult. Furthermore, under these circumstances, microglia can become chronically inflammatory by losing their homeostatic molecular signature and, consequently, their functions during many diseases. Several processes promote the development of neurological disorders and influence their pathological evolution: like the formation of protein aggregates, the accumulation of abnormally modified cellular constituents, the formation and release by injured neurons or synapses of molecules that can dampen neural function, and, of critical importance, the dysregulation of inflammatory control mechanisms. The glucagon-like peptide 1 receptor agonist emerges as a critical tool in treating brain-related inflammatory pathologies, restoring brain cell homeostasis under inflammatory conditions, modulating microglia activity, and decreasing the inflammatory response. This review summarizes recent advances linked to the anti-inflammatory properties of glucagon-like peptide 1 receptor activation in the brain related to multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, vascular dementia, or chronic migraine. Related Articles | Metrics

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Resident immune responses to spinal cord injury: role of astrocytes and microglia Sydney Brockie, Cindy Zhou, Michael G. Fehlings 2024, 19 (8):  1678-1685.  doi: 10.4103/1673-5374.389630 Abstract ( 317 )   PDF (1386KB) ( 154 )   Save Spinal cord injury can be traumatic or non-traumatic in origin, with the latter rising in incidence and prevalence with the aging demographics of our society. Moreover, as the global population ages, individuals with co-existent degenerative spinal pathology comprise a growing number of traumatic spinal cord injury cases, especially involving the cervical spinal cord. This makes recovery and treatment approaches particularly challenging as age and comorbidities may limit regenerative capacity. For these reasons, it is critical to better understand the complex milieu of spinal cord injury lesion pathobiology and the ensuing inflammatory response. This review discusses microglia-specific purinergic and cytokine signaling pathways, as well as microglial modulation of synaptic stability and plasticity after injury. Further, we evaluate the role of astrocytes in neurotransmission and calcium signaling, as well as their border-forming response to neural lesions. Both the inflammatory and reparative roles of these cells have eluded our complete understanding and remain key therapeutic targets due to their extensive structural and functional roles in the nervous system. Recent advances have shed light on the roles of glia in neurotransmission and reparative injury responses that will change how interventions are directed. Understanding key processes and existing knowledge gaps will allow future research to effectively target these cells and harness their regenerative potential. Related Articles | Metrics

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Use of donepezil for neurocognitive recovery after brain injury in adult and pediatric populations: a scoping review Avery L. Miller, Nathan K. Evanson, J. Michael Taylor 2024, 19 (8):  1686-1695.  doi: 10.4103/1673-5374.389628 Abstract ( 121 )   PDF (4165KB) ( 59 )   Save There are few pharmacologic options for the treatment of cognitive deficits associated with traumatic brain injury in pediatric patients. Acetylcholinesterase inhibitors such as donepezil have been evaluated in adult patients after traumatic brain injury, but relatively less is known about the effect in pediatric populations. The goal of this review is to identify knowledge gaps in the efficacy and safety of acetylcholinesterase inhibitors as a potential adjuvant treatment for neurocognitive decline in pediatric patients with traumatic brain injury. Investigators queried PubMed to identify literature published from database inception through June 2023 describing the use of donepezil in young adult traumatic brain injury and pediatric patients with predefined conditions. Based on preselected search criteria, 340 unique papers were selected for title and abstract screening. Thirty-two records were reviewed in full after eliminating preclinical studies and papers outside the scope of the project. In adult traumatic brain injury, we review results from 14 papers detailing 227 subjects where evidence suggests donepezil is well tolerated and shows both objective and patient-reported efficacy for reducing cognitive impairment. In children, 3 papers report on 5 children recovering from traumatic brain injury, showing limited efficacy. An additional 15 pediatric studies conducted in populations at risk for cognitive dysfunction provide a broader look at safety and efficacy in 210 patients in the pediatric age group. Given its promise for efficacy in adults with traumatic brain injury and tolerability in pediatric patients, we believe further study of donepezil for children and adolescents with traumatic brain injury is warranted. Related Articles | Metrics

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The role of snapin in regulation of brain homeostasis Jiawen Li, Xinqi Huang, Yumei An, Xueshi Chen, Yiyang Chen, Mingyuan Xu, Haiyan Shan, Mingyang Zhang 2024, 19 (8):  1696-1701.  doi: 10.4103/1673-5374.389364 Abstract ( 102 )   PDF (1798KB) ( 71 )   Save Brain homeostasis refers to the normal working state of the brain in a certain period, which is important for overall health and normal life activities. Currently, there is a lack of effective treatment methods for the adverse consequences caused by brain homeostasis imbalance. Snapin is a protein that assists in the formation of neuronal synapses and plays a crucial role in the normal growth and development of synapses. Recently, many researchers have reported the association between snapin and neurologic and psychiatric disorders, demonstrating that snapin can improve brain homeostasis. Clinical manifestations of brain disease often involve imbalances in brain homeostasis and may lead to neurological and behavioral sequelae. This article aims to explore the role of snapin in restoring brain homeostasis after injury or diseases, highlighting its significance in maintaining brain homeostasis and treating brain diseases. Additionally, it comprehensively discusses the implications of snapin in other extracerebral diseases such as diabetes and viral infections, with the objective of determining the clinical potential of snapin in maintaining brain homeostasis. Related Articles | Metrics

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Millimetric devices for nerve stimulation: a promising path towards miniaturization Ryan M. Dorrian, Anna V. Leonard, Antonio Lauto 2024, 19 (8):  1702-1706.  doi: 10.4103/1673-5374.389627 Abstract ( 67 )   PDF (1539KB) ( 128 )   Save Nerve stimulation is a rapidly developing field, demonstrating positive outcomes across several conditions. Despite potential benefits, current nerve stimulation devices are large, complicated, and are powered via implanted pulse generators. These factors necessitate invasive surgical implantation and limit potential applications. Reducing nerve stimulation devices to millimetric sizes would make these interventions less invasive and facilitate broader therapeutic applications. However, device miniaturization presents a serious engineering challenge. This review presents significant advancements from several groups that have overcome this challenge and developed millimetric-sized nerve stimulation devices. These are based on antennas, mini-coils, magneto-electric and opto-electronic materials, or receive ultrasound power. We highlight key design elements, findings from pilot studies, and present several considerations for future applications of these devices. Related Articles | Metrics

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Vagus nerve stimulation in cerebral stroke: biological mechanisms, therapeutic modalities, clinical applications, and future directions Li Du, Xuan He, Xiaoxing Xiong, Xu Zhang, Zhihong Jian, Zhenxing Yang 2024, 19 (8):  1707-1717.  doi: 10.4103/1673-5374.389365 Abstract ( 510 )   PDF (1253KB) ( 346 )   Save Stroke is a major disorder of the central nervous system that poses a serious threat to human life and quality of life. Many stroke victims are left with long-term neurological dysfunction, which adversely affects the well-being of the individual and the broader socioeconomic impact. Currently, post-stroke brain dysfunction is a major and difficult area of treatment. Vagus nerve stimulation is a Food and Drug Administration-approved exploratory treatment option for autism, refractory depression, epilepsy, and Alzheimer’s disease. It is expected to be a novel therapeutic technique for the treatment of stroke owing to its association with multiple mechanisms such as altering neurotransmitters and the plasticity of central neurons. In animal models of acute ischemic stroke, vagus nerve stimulation has been shown to reduce infarct size, reduce post-stroke neurological damage, and improve learning and memory capacity in rats with stroke by reducing the inflammatory response, regulating blood-brain barrier permeability, and promoting angiogenesis and neurogenesis. At present, vagus nerve stimulation includes both invasive and non-invasive vagus nerve stimulation. Clinical studies have found that invasive vagus nerve stimulation combined with rehabilitation therapy is effective in improving upper limb motor and cognitive abilities in stroke patients. Further clinical studies have shown that non-invasive vagus nerve stimulation, including ear/cervical vagus nerve stimulation, can stimulate vagal projections to the central nervous system similarly to invasive vagus nerve stimulation and can have the same effect. In this paper, we first describe the multiple effects of vagus nerve stimulation in stroke, and then discuss in depth its neuroprotective mechanisms in ischemic stroke. We go on to outline the results of the current major clinical applications of invasive and non-invasive vagus nerve stimulation. Finally, we provide a more comprehensive evaluation of the advantages and disadvantages of different types of vagus nerve stimulation in the treatment of cerebral ischemia and provide an outlook on the developmental trends. We believe that vagus nerve stimulation, as an effective treatment for stroke, will be widely used in clinical practice to promote the recovery of stroke patients and reduce the incidence of disability. Related Articles | Metrics

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Interplay between microglia and environmental risk factors in Alzheimer’s disease Miaoping Zhang, Chunmei Liang, Xiongjin Chen, Yujie Cai, Lili Cui 2024, 19 (8):  1718-1727.  doi: 10.4103/1673-5374.389745 Abstract ( 253 )   PDF (1252KB) ( 264 )   Save Alzheimer’s disease, among the most common neurodegenerative disorders, is characterized by progressive cognitive impairment. At present, the Alzheimer’s disease main risk remains genetic risks, but major environmental factors are increasingly shown to impact Alzheimer’s disease development and progression. Microglia, the most important brain immune cells, play a central role in Alzheimer’s disease pathogenesis and are considered environmental and lifestyle “sensors.” Factors like environmental pollution and modern lifestyles (e.g., chronic stress, poor dietary habits, sleep, and circadian rhythm disorders) can cause neuroinflammatory responses that lead to cognitive impairment via microglial functioning and phenotypic regulation. However, the specific mechanisms underlying interactions among these factors and microglia in Alzheimer’s disease are unclear. Herein, we: discuss the biological effects of air pollution, chronic stress, gut microbiota, sleep patterns, physical exercise, cigarette smoking, and caffeine consumption on microglia; consider how unhealthy lifestyle factors influence individual susceptibility to Alzheimer’s disease; and present the neuroprotective effects of a healthy lifestyle. Toward intervening and controlling these environmental risk factors at an early Alzheimer’s disease stage, understanding the role of microglia in Alzheimer’s disease development, and targeting strategies to target microglia, could be essential to future Alzheimer’s disease treatments. Related Articles | Metrics

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Impact of increasing one-carbon metabolites on traumatic brain injury outcome using pre-clinical models Sanika M. Joshi, Theresa Currier Thomas, Nafisa M. Jadavji 2024, 19 (8):  1728-1733.  doi: 10.4103/1673-5374.389629 Abstract ( 72 )   PDF (591KB) ( 93 )   Save Traumatic brain injury is a major cause of death and disability worldwide, affecting over 69 million individuals yearly. One-carbon metabolism has been shown to have beneficial effects after brain damage, such as ischemic stroke. However, whether increasing one-carbon metabolite vitamins impacts traumatic brain injury outcomes in patients requires more investigation. The aim of this review is to evaluate how one-carbon metabolites impact outcomes after the onset of traumatic brain injury. PubMed, Web of Science, and Google Scholar databases were searched for studies that examined the impact of B-vitamin supplementation on traumatic brain injury outcomes. The search terms included combinations of the following words: traumatic brain injury, dietary supplementation, one-carbon metabolism, and B-vitamins. The focus of each literature search was basic science data. The year of publication in the literature searches was not limited. Our analysis of the literature has shown that dietary supplementation of B-vitamins has significantly improved the functional and behavioral recovery of animals with traumatic brain injury compared to controls. However, this improvement is dosage-dependent and is contingent upon the onset of supplementation and whether there is a sustained or continuous delivery of vitamin supplementation post-traumatic brain injury. The details of supplementation post-traumatic brain injury need to be further investigated. Overall, we conclude that B-vitamin supplementation improves behavioral outcomes and reduces cognitive impairment post-traumatic brain injury in animal model systems. Further investigation in a clinical setting should be strongly considered in conjunction with current medical treatments for traumatic brain injury-affected individuals. Related Articles | Metrics

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Neutrophil extracellular traps mediate neuro-immunothrombosis Jianbo Lou, Jianning Zhang, Quanjun Deng, Xin Chen 2024, 19 (8):  1734-1740.  doi: 10.4103/1673-5374.389625 Abstract ( 170 )   PDF (959KB) ( 92 )   Save Neutrophil extracellular traps are primarily composed of DNA and histones and are released by neutrophils to promote inflammation and thrombosis when stimulated by various inflammatory reactions. Neutrophil extracellular trap formation occurs through lytic and non-lytic pathways that can be further classified by formation mechanisms. Histones, von Willebrand factor, fibrin, and many other factors participate in the interplay between inflammation and thrombosis. Neuro-immunothrombosis summarizes the intricate interplay between inflammation and thrombosis during neural development and the pathogenesis of neurological diseases, providing cutting-edge insights into post-neurotrauma thrombotic events. The blood-brain barrier defends the brain and spinal cord against external assaults, and neutrophil extracellular trap involvement in blood-brain barrier disruption and immunothrombosis contributes substantially to secondary injuries in neurological diseases. Further research is needed to understand how neutrophil extracellular traps promote blood-brain barrier disruption and immunothrombosis, but recent studies have demonstrated that neutrophil extracellular traps play a crucial role in immunothrombosis, and identified modulators of neuro-immunothrombosis. However, these neurological diseases occur in blood vessels, and the mechanisms are unclear by which neutrophil extracellular traps penetrate the blood-brain barrier to participate in immunothrombosis in traumatic brain injury. This review discusses the role of neutrophil extracellular traps in neuro-immunothrombosis and explores potential therapeutic interventions to modulate neutrophil extracellular traps that may reduce immunothrombosis and improve traumatic brain injury outcomes. Related Articles | Metrics

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Ferroptosis mechanism and Alzheimer’s disease Lina Feng, Jingyi Sun, Ling Xia, Qiang Shi, Yajun Hou, Lili Zhang, Mingquan Li, Cundong Fan, Baoliang Sun 2024, 19 (8):  1741-1750.  doi: 10.4103/1673-5374.389362 Abstract ( 432 )   PDF (2336KB) ( 174 )   Save Regulated cell death is a genetically determined form of programmed cell death that commonly occurs during the development of living organisms. This process plays a crucial role in modulating homeostasis and is evolutionarily conserved across a diverse range of living organisms. Ferroptosis is a classic regulatory mode of cell death. Extensive studies of regulatory cell death in Alzheimer’s disease have yielded increasing evidence that ferroptosis is closely related to the occurrence, development, and prognosis of Alzheimer’s disease. This review summarizes the molecular mechanisms of ferroptosis and recent research advances in the role of ferroptosis in Alzheimer’s disease. Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for Alzheimer’s disease. Related Articles | Metrics

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The combined application of stem cells and three-dimensional bioprinting scaffolds for the repair of spinal cord injury Dingyue Ju, Chuanming Dong 2024, 19 (8):  1751-1758.  doi: 10.4103/1673-5374.385842 Abstract ( 246 )   PDF (3262KB) ( 111 )   Save Spinal cord injury is considered one of the most difficult injuries to repair and has one of the worst prognoses for injuries to the nervous system. Following surgery, the poor regenerative capacity of nerve cells and the generation of new scars can make it very difficult for the impaired nervous system to restore its neural functionality. Traditional treatments can only alleviate secondary injuries but cannot fundamentally repair the spinal cord. Consequently, there is a critical need to develop new treatments to promote functional repair after spinal cord injury. Over recent years, there have been several developments in the use of stem cell therapy for the treatment of spinal cord injury. Alongside significant developments in the field of tissue engineering, three-dimensional bioprinting technology has become a hot research topic due to its ability to accurately print complex structures. This led to the loading of three-dimensional bioprinting scaffolds which provided precise cell localization. These three-dimensional bioprinting scaffolds could repair damaged neural circuits and had the potential to repair the damaged spinal cord. In this review, we discuss the mechanisms underlying simple stem cell therapy, the application of different types of stem cells for the treatment of spinal cord injury, and the different manufacturing methods for three-dimensional bioprinting scaffolds. In particular, we focus on the development of three-dimensional bioprinting scaffolds for the treatment of spinal cord injury.  Related Articles | Metrics

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Dopamine in the prefrontal cortex plays multiple roles in the executive function of patients with Parkinson’s disease Zihang Zhou, Yalong Yan, Heng Gu, Ruiao Sun, Zihan Liao, Ke Xue, Chuanxi Tang 2024, 19 (8):  1759-1767.  doi: 10.4103/1673-5374.389631 Abstract ( 199 )   PDF (1130KB) ( 112 )   Save Parkinson’s disease can affect not only motor functions but also cognitive abilities, leading to cognitive impairment. One common issue in Parkinson’s disease with cognitive dysfunction is the difficulty in executive functioning. Executive functions help us plan, organize, and control our actions based on our goals. The brain area responsible for executive functions is called the prefrontal cortex. It acts as the command center for the brain, especially when it comes to regulating executive functions. The role of the prefrontal cortex in cognitive processes is influenced by a chemical messenger called dopamine. However, little is known about how dopamine affects the cognitive functions of patients with Parkinson’s disease. In this article, the authors review the latest research on this topic. They start by looking at how the dopaminergic system, is altered in Parkinson’s disease with executive dysfunction. Then, they explore how these changes in dopamine impact the synaptic structure, electrical activity, and connection components of the prefrontal cortex. The authors also summarize the relationship between Parkinson’s disease and dopamine-related cognitive issues. This information may offer valuable insights and directions for further research and improvement in the clinical treatment of cognitive impairment in Parkinson’s disease. Related Articles | Metrics

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Physical exercise and synaptic protection in human and pre-clinical models of multiple sclerosis Federica Azzolini, Ettore Dolcetti, Antonio Bruno, Valentina Rovella, Diego Centonze, Fabio Buttari 2024, 19 (8):  1768-1771.  doi: 10.4103/1673-5374.389359 Abstract ( 102 )   PDF (2615KB) ( 41 )   Save In multiple sclerosis, only immunomodulatory and immunosuppressive drugs are recognized as disease-modifying therapies. However, in recent years, several data from pre-clinical and clinical studies suggested a possible role of physical exercise as disease-modifying therapy in multiple sclerosis. Current evidence is sparse and often conflicting, and the mechanisms underlying the neuroprotective and antinflammatory role of exercise in multiple sclerosis have not been fully elucidated. Data, mainly derived from pre-clinical studies, suggest that exercise could enhance long-term potentiation and thus neuroplasticity, could reduce neuroinflammation and synaptopathy, and dampen astrogliosis and microgliosis. In humans, most trials focused on direct clinical and MRI outcomes, as investigating synaptic, neuroinflammatory, and pathological changes is not straightforward compared to animal models. The present review analyzed current evidence and limitations in research concerning the potential disease-modifying therapy effects of exercise in multiple sclerosis in animal models and human studies.  Related Articles | Metrics

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High-frequency repetitive transcranial magnetic stimulation promotes neural stem cell proliferation after ischemic stroke Jing Luo, Yuan Feng, Zhongqiu Hong, Mingyu Yin, Haiqing Zheng, Liying Zhang, Xiquan Hu 2024, 19 (8):  1772-1780.  doi: 10.4103/1673-5374.389303 Abstract ( 184 )   PDF (10220KB) ( 120 )   Save Proliferation of neural stem cells is crucial for promoting neuronal regeneration and repairing cerebral infarction damage. Transcranial magnetic stimulation (TMS) has recently emerged as a tool for inducing endogenous neural stem cell regeneration, but its underlying mechanisms remain unclear. In this study, we found that repetitive TMS effectively promotes the proliferation of oxygen-glucose deprived neural stem cells. Additionally, repetitive TMS reduced the volume of cerebral infarction in a rat model of ischemic stroke caused by middle cerebral artery occlusion, improved rat cognitive function, and promoted the proliferation of neural stem cells in the ischemic penumbra. RNA-sequencing found that repetitive TMS activated the Wnt signaling pathway in the ischemic penumbra of rats with cerebral ischemia. Furthermore, PCR analysis revealed that repetitive TMS promoted AKT phosphorylation, leading to an increase in mRNA levels of cell cycle-related proteins such as Cdk2 and Cdk4. This effect was also associated with activation of the glycogen synthase kinase 3β/β-catenin signaling pathway, which ultimately promotes the proliferation of neural stem cells. Subsequently, we validated the effect of repetitive TMS on AKT phosphorylation. We found that repetitive TMS promoted Ca2+ influx into neural stem cells by activating the P2 calcium channel/calmodulin pathway, thereby promoting AKT phosphorylation and activating the glycogen synthase kinase 3β/β-catenin pathway. These findings indicate that repetitive TMS can promote the proliferation of endogenous neural stem cells through a Ca2+ influx-dependent phosphorylated AKT/glycogen synthase kinase 3β/β-catenin signaling pathway. This study has produced pioneering results on the intrinsic mechanism of repetitive TMS to promote neural function recovery after ischemic stroke. These results provide a strong scientific foundation for the clinical application of repetitive TMS. Moreover, repetitive TMS treatment may not only be an efficient and potential approach to support neurogenesis for further therapeutic applications, but also provide an effective platform for the expansion of neural stem cells. Related Articles | Metrics

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Two-photon live imaging of direct glia-to-neuron conversion in the mouse cortex Zongqin Xiang, Shu He, Rongjie Chen, Shanggong Liu, Minhui Liu, Liang Xu, Jiajun Zheng, Zhouquan Jiang, Long Ma, Ying Sun, Yongpeng Qin, Yi Chen, Wen Li, Xiangyu Wang, Gong Chen, Wenliang Lei 2024, 19 (8):  1781-1788.  doi: 10.4103/1673-5374.386401 Abstract ( 226 )   PDF (111556KB) ( 98 )   Save Over the past decade, a growing number of studies have reported transcription factor-based in situ reprogramming that can directly convert endogenous glial cells into functional neurons as an alternative approach for neuroregeneration in the adult mammalian central nervous system. However, many questions remain regarding how a terminally differentiated glial cell can transform into a delicate neuron that forms part of the intricate brain circuitry. In addition, concerns have recently been raised around the absence of astrocyte-to-neuron conversion in astrocytic lineage-tracing mice. In this study, we employed repetitive two-photon imaging to continuously capture the in situ astrocyte-to-neuron conversion process following ectopic expression of the neural transcription factor NeuroD1 in both proliferating reactive astrocytes and lineage-traced astrocytes in the mouse cortex. Time-lapse imaging over several weeks revealed the step-by-step transition from a typical astrocyte with numerous short, tapered branches to a typical neuron with a few long neurites and dynamic growth cones that actively explored the local environment. In addition, these lineage-converting cells were able to migrate radially or tangentially to relocate to suitable positions. Furthermore, two-photon Ca2+ imaging and patch-clamp recordings confirmed that the newly generated neurons exhibited synchronous calcium signals, repetitive action potentials, and spontaneous synaptic responses, suggesting that they had made functional synaptic connections within local neural circuits. In conclusion, we directly visualized the step-by-step lineage conversion process from astrocytes to functional neurons in vivo and unambiguously demonstrated that adult mammalian brains are highly plastic with respect to their potential for neuroregeneration and neural circuit reconstruction. Related Articles | Metrics

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How do lateral septum projections to the ventral CA1 influence sociability? Dan Wang, Di Zhao, Wentao Wang, Fengai Hu, Minghu Cui, Jing Liu, Fantao Meng, Cuilan Liu, Changyun Qiu, Dunjiang Liu, Zhicheng Xu, Yameng Wang, Yu Zhang, Wei Li, Chen Li 2024, 19 (8):  1789-1801.  doi: 10.4103/1673-5374.389304 Abstract ( 123 )   PDF (35913KB) ( 42 )   Save Social dysfunction is a risk factor for several neuropsychiatric illnesses. Previous studies have shown that the lateral septum (LS)-related pathway plays a critical role in mediating social behaviors. However, the role of the connections between the LS and its downstream brain regions in social behaviors remains unclear. In this study, we conducted a three-chamber test using electrophysiological and chemogenetic approaches in mice to determine how LS projections to ventral CA1 (vCA1) influence sociability. Our results showed that gamma-aminobutyric acid (GABA)-ergic neurons were activated following social experience, and that social behaviors were enhanced by chemogenetic modulation of these neurons. Moreover, LS GABAergic neurons extended their functional neural connections via vCA1 glutamatergic pyramidal neurons, and regulating LSGABA→vCA1Glu neural projections affected social behaviors, which were impeded by suppressing LS-projecting vCA1 neuronal activity or inhibiting GABAA receptors in vCA1. These findings support the hypothesis that LS inputs to the vCA1 can control social preferences and social novelty behaviors. These findings provide new insights regarding the neural circuits that regulate sociability. Related Articles | Metrics

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Lupenone improves motor dysfunction in spinal cord injury mice through inhibiting the inflammasome activation and pyroptosis in microglia via the nuclear factor kappa B pathway Fudong Li, Xiaofei Sun, Kaiqiang Sun, Fanqi Kong, Xin Jiang, Qingjie Kong 2024, 19 (8):  1802-1811.  doi: 10.4103/1673-5374.389302 Abstract ( 113 )   PDF (11182KB) ( 51 )   Save Spinal cord injury-induced motor dysfunction is associated with neuroinflammation. Studies have shown that the triterpenoid lupenone, a natural product found in various plants, has a remarkable anti-inflammatory effect in the context of chronic inflammation. However, the effects of lupenone on acute inflammation induced by spinal cord injury remain unknown. In this study, we established an impact-induced mouse model of spinal cord injury, and then treated the injured mice with lupenone (8 mg/kg, twice a day) by intraperitoneal injection. We also treated BV2 cells with lipopolysaccharide and adenosine 5′-triphosphate to simulate the inflammatory response after spinal cord injury. Our results showed that lupenone reduced IκBα activation and p65 nuclear translocation, inhibited NLRP3 inflammasome function by modulating nuclear factor kappa B, and enhanced the conversion of proinflammatory M1 microglial cells into anti-inflammatory M2 microglial cells. Furthermore, lupenone decreased NLRP3 inflammasome activation, NLRP3-induced microglial cell polarization, and microglia pyroptosis by inhibiting the nuclear factor kappa B pathway. These findings suggest that lupenone protects against spinal cord injury by inhibiting inflammasomes. Related Articles | Metrics

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RNA sequencing of exosomes secreted by fibroblast and Schwann cells elucidates mechanisms underlying peripheral nerve regeneration Xinyang Zhou, Yehua Lv, Huimin Xie, Yan Li, Chang Liu, Mengru Zheng, Ronghua Wu, Songlin Zhou, Xiaosong Gu, Jingjing Li, Daguo Mi 2024, 19 (8):  1812-1821.  doi: 10.4103/1673-5374.387980 Abstract ( 107 )   PDF (8469KB) ( 135 )   Save Exosomes exhibit complex biological functions and mediate a variety of biological processes, such as promoting axonal regeneration and functional recovery after injury. Long non-coding RNAs (lncRNAs) have been reported to play a crucial role in axonal regeneration. However, the role of the lncRNA-microRNA-messenger RNA (mRNA)-competitive endogenous RNA (ceRNA) network in exosome-mediated axonal regeneration remains unclear. In this study, we performed RNA transcriptome sequencing analysis to assess mRNA expression patterns in exosomes produced by cultured fibroblasts (FC-EXOs) and Schwann cells (SC-EXOs). Differential gene expression analysis, Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis, and protein-protein interaction network analysis were used to explore the functions and related pathways of RNAs isolated from FC-EXOs and SC-EXOs. We found that the ribosome-related central gene Rps5 was enriched in FC-EXOs and SC-EXOs, which suggests that it may promote axonal regeneration. In addition, using the miRWalk and Starbase prediction databases, we constructed a regulatory network of ceRNAs targeting Rps5, including 27 microRNAs and five lncRNAs. The ceRNA regulatory network, which included Ftx and Miat, revealed that exsosome-derived Rps5 inhibits scar formation and promotes axonal regeneration and functional recovery after nerve injury. Our findings suggest that exosomes derived from fibroblast and Schwann cells could be used to treat injuries of peripheral nervous system. Related Articles | Metrics

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Neutrophil peptide 1 accelerates the clearance of degenerative axons during Wallerian degeneration by activating macrophages after peripheral nerve crush injury Yuhui Kou, Yusong Yuan, Qicheng Li, Wenyong Xie, Hailin Xu, Na Han 2024, 19 (8):  1822-1827.  doi: 10.4103/1673-5374.387978 Abstract ( 116 )   PDF (2831KB) ( 128 )   Save Macrophages play an important role in peripheral nerve regeneration, but the specific mechanism of regeneration is still unclear. Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide closely involved in peripheral nerve regeneration. However, the mechanism by which neutrophil peptide 1 enhances nerve regeneration remains unclear. This study was designed to investigate the relationship between neutrophil peptide 1 and macrophages in vivo and in vitro in peripheral nerve crush injury. The functions of RAW 264.7 cells were elucidated by Cell Counting Kit-8 assay, flow cytometry, migration assays, phagocytosis assays, immunohistochemistry and enzyme-linked immunosorbent assay. Axonal debris phagocytosis was observed using the CUBIC (Clear, Unobstructed Brain/Body Imaging Cocktails and Computational analysis) optical clearing technique during Wallerian degeneration. Macrophage inflammatory factor expression in different polarization states was detected using a protein chip. The results showed that neutrophil peptide 1 promoted the proliferation, migration and phagocytosis of macrophages, and CD206 expression on the surface of macrophages, indicating M2 polarization. The axonal debris clearance rate during Wallerian degeneration was enhanced after neutrophil peptide 1 intervention. Neutrophil peptide 1 also downregulated inflammatory factors interleukin-1α, -6, -12, and tumor necrosis factor-α in vivo and in vitro. Thus, the results suggest that neutrophil peptide 1 activates macrophages and accelerates Wallerian degeneration, which may be one mechanism by which neutrophil peptide 1 enhances peripheral nerve regeneration. Related Articles | Metrics

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A novel mechanism of PHB2-mediated mitophagy participating in the development of Parkinson’s disease Yongjiang Zhang, Shiyi Yin, Run Song, Xiaoyi Lai, Mengmeng Shen, Jiannan Wu, Junqiang Yan 2024, 19 (8):  1828-1834.  doi: 10.4103/1673-5374.389356 Abstract ( 181 )   PDF (6620KB) ( 512 )   Save Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson’s disease, but the regulatory mechanism remains elusive. Prohibitin-2 (PHB2) is a newly discovered autophagy receptor in the mitochondrial inner membrane, and its role in Parkinson’s disease remains unclear. Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is a factor that regulates cell fate during endoplasmic reticulum stress. Parkin is regulated by PERK and is a target of the unfolded protein response. It is unclear whether PERK regulates PHB2-mediated mitophagy through Parkin. In this study, we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson’s disease. We used adeno-associated virus to knockdown PHB2 expression. Our results showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson’s disease. Overexpression of PHB2 inhibited these abnormalities. We also established a 1-methyl-4-phenylpyridine (MPP+)-induced SH-SY5Y cell model of Parkinson’s disease. We found that overexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3, and promoted mitophagy. In addition, MPP+ regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK. These findings suggest that PHB2 participates in the development of Parkinson’s disease by interacting with endoplasmic reticulum stress and Parkin. Related Articles | Metrics

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Promotion of structural plasticity in area V2 of visual cortex prevents against object recognition memory deficits in aging and Alzheimer’s disease rodents Irene Navarro-Lobato, Mariam Masmudi-Martín, Manuel F. López-Aranda, Juan F. López-Téllez, Gloria Delgado, Pablo Granados-Durán, Celia Gaona-Romero, Marta Carretero-Rey, Sinforiano Posadas, María E. Quiros-Ortega, Zafar U. Khan 2024, 19 (8):  1835-1841.  doi: 10.4103/1673-5374.389301 Abstract ( 111 )   PDF (1264KB) ( 90 )   Save Memory deficit, which is often associated with aging and many psychiatric, neurological, and neurodegenerative diseases, has been a challenging issue for treatment. Up till now, all potential drug candidates have failed to produce satisfactory effects. Therefore, in the search for a solution, we found that a treatment with the gene corresponding to the RGS14414 protein in visual area V2, a brain area connected with brain circuits of the ventral stream and the medial temporal lobe, which is crucial for object recognition memory (ORM), can induce enhancement of ORM. In this study, we demonstrated that the same treatment with RGS14414 in visual area V2, which is relatively unaffected in neurodegenerative diseases such as Alzheimer’s disease, produced long-lasting enhancement of ORM in young animals and prevent ORM deficits in rodent models of aging and Alzheimer’s disease. Furthermore, we found that the prevention of memory deficits was mediated through the upregulation of neuronal arborization and spine density, as well as an increase in brain-derived neurotrophic factor (BDNF). A knockdown of BDNF gene in RGS14414-treated aging rats and Alzheimer’s disease model mice caused complete loss in the upregulation of neuronal structural plasticity and in the prevention of ORM deficits. These findings suggest that BDNF-mediated neuronal structural plasticity in area V2 is crucial in the prevention of memory deficits in RGS14414-treated rodent models of aging and Alzheimer’s disease. Therefore, our findings of RGS14414 gene-mediated activation of neuronal circuits in visual area V2 have therapeutic relevance in the treatment of memory deficits. Related Articles | Metrics

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Circulating proteomic biomarkers for diagnosing sporadic amyotrophic lateral sclerosis: a cross-sectional study Lu He, Qinming Zhou, Chaoyang Xiu, Yaping Shao, Dingding Shen, Huanyu Meng, Weidong Le, Sheng Chen 2024, 19 (8):  1842-1848.  doi: 10.4103/1673-5374.389357 Abstract ( 88 )   PDF (9319KB) ( 28 )   Save Biomarkers are required for the early detection, prognosis prediction, and monitoring of amyotrophic lateral sclerosis, a progressive disease. Proteomics is an unbiased and quantitative method that can be used to detect neurochemical signatures to aid in the identification of candidate biomarkers. In this study, we used a label-free quantitative proteomics approach to screen for substantially differentially regulated proteins in ten patients with sporadic amyotrophic lateral sclerosis compared with five healthy controls. Substantial upregulation of serum proteins related to multiple functional clusters was observed in patients with sporadic amyotrophic lateral sclerosis. Potential biomarkers were selected based on functionality and expression specificity. To validate the proteomics profiles, blood samples from an additional cohort comprising 100 patients with sporadic amyotrophic lateral sclerosis and 100 healthy controls were subjected to enzyme-linked immunosorbent assay. Eight substantially upregulated serum proteins in patients with sporadic amyotrophic lateral sclerosis were selected, of which the cathelicidin-related antimicrobial peptide demonstrated the best discriminative ability between patients with sporadic amyotrophic lateral sclerosis and healthy controls (area under the curve [AUC] = 0.713, P < 0.0001). To further enhance diagnostic accuracy, a multi-protein combined discriminant algorithm was developed incorporating five proteins (hemoglobin beta, cathelicidin-related antimicrobial peptide, talin-1, zyxin, and translationally-controlled tumor protein). The algorithm achieved an AUC of 0.811 and a P-value of < 0.0001, resulting in 79% sensitivity and 71% specificity for the diagnosis of sporadic amyotrophic lateral sclerosis. Subsequently, the ability of candidate biomarkers to discriminate between early-stage amyotrophic lateral sclerosis patients and controls, as well as patients with different disease severities, was examined. A two-protein panel comprising talin-1 and translationally-controlled tumor protein effectively distinguished early-stage amyotrophic lateral sclerosis patients from controls (AUC = 0.766, P < 0.0001). Moreover, the expression of three proteins (FK506 binding protein 1A, cathelicidin-related antimicrobial peptide, and hemoglobin beta-1) was found to increase with disease progression. The proteomic signatures developed in this study may help facilitate early diagnosis and monitor the progression of sporadic amyotrophic lateral sclerosis when used in combination with current clinical-based parameters. Related Articles | Metrics

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P-aminobenzoic acid promotes retinal regeneration through activation of Ascl1a in zebrafish Meihui He, Mingfang Xia, Qian Yang, Xingyi Chen, Haibo Li, Xiaobo Xia 2024, 19 (8):  1849-1856.  doi: 10.4103/1673-5374.389646 Abstract ( 120 )   PDF (7568KB) ( 111 )   Save The retina of zebrafish can regenerate completely after injury. Multiple studies have demonstrated that metabolic alterations occur during retinal damage; however to date no study has identified a link between metabolites and retinal regeneration of zebrafish. Here, we performed an unbiased metabolome sequencing in the N-methyl-D-aspartic acid-damaged retinas of zebrafish to demonstrate the metabolomic mechanism of retinal regeneration. Among the differentially-expressed metabolites, we found a significant decrease in p-aminobenzoic acid in the N-methyl-D-aspartic acid-damaged retinas of zebrafish. Then, we investigated the role of p-aminobenzoic acid in retinal regeneration in adult zebrafish. Importantly, p-aminobenzoic acid activated Achaetescute complex-like 1a expression, thereby promoting Müller glia reprogramming and division, as well as Müller glia-derived progenitor cell proliferation. Finally, we eliminated folic acid and inflammation as downstream effectors of PABA and demonstrated that PABA had little effect on Müller glia distribution. Taken together, these findings show that PABA contributes to retinal regeneration through activation of Achaetescute complex-like 1a expression in the N-methyl-D-aspartic acid-damaged retinas of zebrafish.  Related Articles | Metrics