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15 October 2024, Volume 19 Issue 10 Previous Issue   

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Modulation of p75 neurotrophin receptor mitigates brain damage following ischemic stroke in mice Golnoush Mirzahosseini, Tauheed Ishrat 2024, 19 (10):  2093-2094.  doi: 10.4103/1673-5374.392860 Abstract ( 143 )   PDF (515KB) ( 123 )   Save Stroke is a significant leading cause of death and disability in the United States (Tsao et al., 2022). Approximately 87% of strokes fall into the ischemic category, mainly caused by arterial blockage (Jayaraj et al., 2019). Although the only FDA-approved effective medication is tissue plasminogen activator (tPA), it should be administrated within 4.5 hours of ischemic stroke. Furthermore, tPA has been an integral part of managing acute ischemic stroke. However, it increases the development of intracerebral hemorrhage (Goncalves et al., 2022). Therefore, discovering a novel neuroprotective drug is a high clinical need. In recent years, there has been a significant increase in the utilization of thrombectomy procedures. Related Articles | Metrics

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Conformational dynamics as an intrinsic determinant of prion protein misfolding and neurotoxicity Alessandro Cembran, Pedro Fernandez-Funez 2024, 19 (10):  2095-2096.  doi: 0.4103/1673-5374.391332 Abstract ( 48 )   PDF (1122KB) ( 27 )   Save The prion protein (PrP) is the key molecular and pathological mediator of prion diseases, a heterogeneous group of brain disorders with fatal outcomes. Prion diseases are rare but deserve special attention because of their unique familial, sporadic, and transmissible etiologies, all caused by a single agent: misfolded conformations of PrP. The novel transmission of prion diseases captured the imagination of generations of scientists set on uncovering the molecular mechanisms underlying protein misfolding: seeded polymerization. This novel mechanism now appears to underlie not only prion diseases but also a group of highly prevalent brain disorders that include Alzheimer’s and Parkinson’s diseases among others, making the study of PrP misfolding highly significant. PrP is a small, secreted protein attached to the extracellular aspect of the membrane. It contains an unstructured N-terminus and a small globular domain with three α-helices and a short β-sheet. Misfolded and aggregated PrP into macromolecular assemblies is assumed to underlie both neuropathology and transmissibility of prion diseases. Recent models propose that different PrP species, including soluble, insoluble, and protease-resistant assemblies, are responsible for different aspects of prion disease pathology. Regardless of the identity of the PrP species responsible for pathology, the key pathological event is the misfolding of this abundant protein. The overall structural differences between physiological PrPC (cellular) and pathogenic PrPres (protease resistant) are well documented, including an increase in β-sheet content (from 3% to > 40%) that promotes self-assembly (Pan et al., 1993; Perez et al., 2010; Christen et al., 2013). Despite the extensive resources generated to examine PrP structure, we still have a limited knowledge about the molecular mechanism regulating PrP conformational dynamics and the initiation of misfolding. Related Articles | Metrics

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Exploring the synergy of the eye-brain connection: neuromodulation approaches for neurodegenerative disorders through transcorneal electrical stimulation Antara Verma, Stephen K. Agadagba, Leanne Lai-Hang Chan 2024, 19 (10):  2097-2098.  doi: 10.4103/1673-5374.392877 Abstract ( 129 )   PDF (747KB) ( 87 )   Save The connection and interaction between the eye and the brain are crucial to understanding brain disorders (Marchesi et al., 2021). Both the eye and the brain have a limited regenerative capacity as there are few progenitor cells, and nerve cells do not replicate. Hence, neurodegeneration implicates irreversible damage to the central nervous system, as observed in several neurodegenerative diseases (Marchesi et al., 2021). The eye serves as an easily accessible extension of the brain that enables the discovery and non-invasive visualization of possible biomarkers for several neurodegenerative and neurological diseases (London et al., 2013). There has been a recent focus on exploiting the eye-brain connection for therapeutic interventions to treat such diseases. Electrical stimulation remains the oldest and most common method of neuromodulation. However, most forms of electrical stimulation are predominantly invasive (such as deep brain stimulation and motor cortex stimulation) and have numerous postsurgical complications, while other non-invasive forms (such as transcranial electrical stimulation and vagus nerve stimulation) elicit large variability in response to stimulation (Reed and Cohen Kadosh, 2018). Thus, there is a need for novel and more effective non-invasive electrical neuromodulation approaches. In this regard, transcorneal electrical stimulation (TES) is an emerging technique to modulate brain networks in neurodegenerative disorders via non-invasive stimulation of the eye. Electrophysiological, molecular, and behavioral evidence strongly support TES as a neuromodulatory method for brain regions beyond the visual cortex (Yu et al., 2022). This presents a positive outlook for the future of TES and its development as a sought-after neuromodulatory technique. This article provides a summary of the eye-brain connection, highlighting its significance in neurodegenerative diseases. Furthermore, recent advancements in neuromodulation via TES, with an emphasis on electrophysiological evidence, are reported. Related Articles | Metrics

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Pathogenic contribution of cholesteryl ester accumulation in the brain to neurodegenerative disorders Michiko Shirane 2024, 19 (10):  2099-2100.  doi: 10.4103/1673-5374.392878 Abstract ( 70 )   PDF (582KB) ( 32 )   Save Cholesteryl esters (CEs) have been increasingly implicated in neurodegenerative disorders such as Alzheimer’s disease (AD). Alois Alzheimer noted three prominent neuropathologic features in his original analysis of the AD brain: senile plaques, neurofibrillary tangles, and lipid granule accumulation. Senile plaques, which are aggregates of amyloid-beta (Aβ), and neurofibrillary tangles, which are aggregates of phosphorylated tau, have been regarded as more consistent characteristics of the AD brain compared with lipid granule accumulation and thus have been studied more intensively (Foley, 2010). However, more recent large-scale genetic studies have revealed that a major risk factor for late-onset AD (LOAD) is the APOE4 variant allele of the gene for apolipoprotein E (APOE), a protein that plays an important role in cholesterol metabolism and lipid transport. In addition, individuals who harbor variants of the gene for triggering receptor expressed on myeloid cells 2 (TREM2), an immune receptor protein expressed in microglia, have also been known to be at higher risk for the development of LOAD. Such findings have led to an increased focus on defective lipid metabolism and inflammation in the brain as potential pathological mechanisms of LOAD (Shi and Holtzman, 2018). The accumulation of CEs has also recently been identified in postmortem brain tissue of individuals with LOAD as well as in the brain of AD model mice, such as those that overexpress the Aβ precursor protein (APP) or which are deficient in APOE or TREM2 (Chan et al., 2012; Nugent et al., 2020). Furthermore, the accumulation of phosphorylated tau as well as the release of Aβ was shown to be promoted by CEs in neurons that were derived from induced pluripotent stem cells of individuals with AD and which harbored an extra copy of the APP gene (van der Kant et al., 2019). CEs are highly hydrophobic lipids and are the main components of both high-density lipoprotein (HDL) outside of cells and lipid droplets (LDs) within cells. Potential causes of CE accumulation in the AD brain include impairment of the clearance of phagocytosed cholesterol contained in myelin debris, as has been demonstrated in TREM2-deficient mice, as well as defective cholesterol transport in the brain, as has been shown in APOE-deficient mice (Nugent et al., 2020). Related Articles | Metrics

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Cognition and movement in neurodegenerative disorders: a dynamic duo#br# Marit F.L. Ruitenberg 2024, 19 (10):  2101-2102.  doi: 10.4103/1673-5374.392879 Abstract ( 80 )   PDF (642KB) ( 33 )   Save People with neurodegenerative disorders often experience problems across a variety of functional domains, including cognition, movement, and psychosocial functioning. The classification of these disorders is based on the phenotypical manifestations that represent the most prominent clinical features. For example, Parkinson’s disease and Huntington’s disease are typically regarded as movement disorders, whereas Alzheimer’s disease (AD) and other dementias are regarded as cognitive disorders. A problem with this classification is that it seems to disregard the fact that cognition and movement are actually strongly linked – successful motor performance does not only require the direct, physical control of muscles by the musculoskeletal system to generate movement and stability, but also involves cognitive control processes that allow us to engage in goal-directed behavior in the face of uncertain and/or changing environments (Abrahamse et al., 2013; McDougle et al., 2016). As a result, it seems difficult (if not impossible) to separate between “pure” motor or cognitive conditions. In this perspective article, I therefore propose that we should consider abandoning the classical movement versus cognitive disorder dichotomy when it comes to classifying neurodegenerative diseases. Related Articles | Metrics

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Probing the endoplasmic reticulum-mitochondria interaction in Alzheimer’s disease: searching far and wide Giulia Dematteis, Laura Tapella, Dmitry Lim 2024, 19 (10):  2103-2104.  doi: 10.4103/1673-5374.392880 Abstract ( 138 )   PDF (1484KB) ( 77 )   Save Alzheimer’s disease (AD) is the most frequent form of dementia in elderly people and is an incurable disease with an exponentially growing number of cases. Extracellular deposition of amyloid-β (Aβ) plaques and intraneuronal formation of neurofibrillary tangles represent neuropathological hallmarks of AD. A high failure rate of clinical trials, testing drugs aimed at either removal of Aβ or normalization of neuronal functions, suggests that the amyloid cascade hypothesis is not able to explain the complexity of AD pathogenesis, and the role of non-neuronal cells of the central nervous system, such as astroglial cells, should be considered. A significant advance in AD research has been the understanding that the pathogenesis, at a cellular level, starts much earlier than the appearance of clinical symptoms. Cellular remodeling includes alteration of protein synthesis, folding, and degradation, dysregulation of calcium homeostasis and signaling, mitochondrial alterations accompanied by bioenergetic deficit, and accumulation of reactive oxygen species. These alterations have been exploited to formulate numerous AD hypotheses, including the amyloid cascade and the inflammatory, vascular, and infectious factors, which, traditionally, have been developed and interpreted through the lens of neuronal dysfunction, while alterations of glial cells, such as astrocytes have been largely overlooked (Verkhratsky et al., 2019; Lim et al., 2023). Recently, dysregulation of inter-organellar communication, in particular, the mitochondria-endoplasmic reticulum (ER) interaction, both in neurons and non-neuronal cells, came to age as a potential cause of cellular dysfunction in AD and other diseases, such as Parkinson’s disease (Paillusson et al., 2016; Area-Gomez and Schon, 2017; Lim et al., 2021).  Related Articles | Metrics

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Music as medicine for traumatic brain injury: a perspective on future research directions Anthony E. Kline, Eleni H. Moschonas, Corina O. Bondi 2024, 19 (10):  2105-2106.  doi: 10.4103/1673-5374.392862 Abstract ( 101 )   PDF (347KB) ( 37 )   Save Traumatic brain injury (TBI) impacts 69 million individuals globally each year and is a leading cause of death and disability (Dewan et al., 2019). The majority of moderate-to-severe TBI survivors endure long-lasting disturbances in motor, cognitive, and affect that negatively impacts their life. Although a plethora of research on pharmacological interventions for TBI has been conducted, none has translated to the clinic, thus advocating for the evaluation of nonpharmacological therapeutic approaches that may increase translational success. Related Articles | Metrics

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Motor cortical circuit adaptations in parkinsonism Hong-Yuan Chu 2024, 19 (10):  2107-2108.  doi: 10.4103/1673-5374.392884 Abstract ( 81 )   PDF (1497KB) ( 29 )   Save Parkinson’s disease is a chronic and progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, which leads to the featured motor impairment of parkinsonism, including akinesia, bradykinesia, rigidity, and tremor (McGregor and Nelson, 2019). The natural progression of Parkinson’s disease can last for decades in humans, during which dopamine levels in the brain continue to drop as a consequence of the gradual degeneration of midbrain dopaminergic cells and their axonal projections to the striatum. At the same time, other parts of the brain adapt to the immediate consequences of the decreased dopamine levels. Some adaptations can act as compensatory mechanisms, delaying the onset of motor impairments. However, motor deficits become clinically noticeable when such adaptations fail to counteract the damages associated with the loss of dopamine. Over the last two decades, a series of adaptative changes at the molecular, cellular, and synaptic levels throughout the basal ganglia circuits have been reported (McGregor and Nelson, 2019; Chu, 2020). However, it remains undefined whether loss of dopamine also triggers similar adaptative changes in brain regions downstream of the basal ganglia. Related Articles | Metrics

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Actin(g) toward a revised understanding of the role of cytoskeletal dynamics in neuronal bioenergetics Sabrina M. Holland, Gianluca Gallo 2024, 19 (10):  2109-2110.  doi: 10.4103/1673-5374.392863 Abstract ( 107 )   PDF (830KB) ( 42 )   Save Neurons are energy-demanding cells. Disruptions in energy metabolism can quickly interrupt neuronal function, leading to cell death and neurodegeneration. For instance, ischemia rapidly depletes adenosine triphosphate (ATP) thereby disrupting energy-dependent cellular processes crucial for homeostasis, and axon degeneration is preceded by a collapse of axonal ATP levels. The initial extension and regeneration of axons are also considered to require significant bioenergetic utilization. Therefore, understanding neuronal bioenergetics and the regulation of intracellular ATP levels is crucial for both our basic understanding of neuronal function and ultimately developing new therapies to facilitate neuronal regeneration after injuries. Work performed over 20 years ago, using available approaches, lead to the hypothesis that actin filament dynamics are a major “sink” of ATP utilization in embryonic ciliary ganglion neurons (Bernstein and Bamburg, 2003) and platelets (Daniel et al., 1986). However, neither of these studies directly measured ATP and relied on indirect measurements or quantitative estimation of ATP. Our recent work (Holland and Gallo, 2023) revisited this hypothesis using modern live imaging ratiometric intra-cellular reporters of ATP and the ATP/ADP ratio and failed to obtain data consistent with the hypothesis that actin filament dynamics are a sink of ATP utilization in embryonic sensory neurons. Thus, these recent data indicate that the contribution of cytoskeletal dynamics and other bioenergetic sinks would benefit from additional scrutiny. Related Articles | Metrics

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Going straight for the gut: gut-brain axis pathology and treatment of Parkinson’s disease Dominique Ebedes, Cesar V. Borlongan 2024, 19 (10):  2111-2112.  doi: 10.4103/1673-5374.392885 Abstract ( 167 )   PDF (432KB) ( 57 )   Save This perspective focuses on the recent literature regarding the role of the gut-brain axis (GBA) in fecal microbiota transplantation (FMT) and stem cell therapy (SCT) in Parkinson’s disease (PD). PD is the second most common neurodegenerative disease in the United States, yet therapies remain limited. Current research suggests that the GBA may play a role in the pathogenesis of PD. GBA-based FMT as well as SCT offer promising new avenues for PD treatment. Probing the interactions between FMT and SCT with the GBA may reveal novel therapeutics for PD. Related Articles | Metrics

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Current perspective on amyloid aggregation accelerating properties of the artificial butter flavoring, diacetyl Ashish P. Vartak, Swati S. More 2024, 19 (10):  2113-2114.  doi: 10.4103/1673-5374.392882 Abstract ( 80 )   PDF (1196KB) ( 29 )   Save The amyloid—what peptide can resist its entropic bliss? Without kinetic barricades and chaperones, most peptides would simply tumble down that precipice. The amyloid-β (Aβ) peptides are understood to underlie the hallmark pathology of Alzheimer’s disease (AD) and are considered one of the causative factors for neurodegeneration and cognitive impairment. AD affects critical connected structures within the brain that are responsible for memory, language, and social behavior. Various isoforms of Aβ peptides are produced by proteolytic cleavage of the transmembrane amyloid precursor protein (APP) by secretases, which dictates the amyloidogenic fate of the released product. Those released from α-secretase cleavage appear to be non-amyloidogenic, while β-secretase cleavage that releases fragments with intact N-termini is amyloidogenic. Further diversification occurs also through a slew of post-translational modifications, such as methionine25 oxidation and aspartate racemization, producing fragments with varying amyloidogenic tendencies. Amongst all of these isoforms, peptides Aβ1–42 and Aβ1–40 show higher propensity for aggregation, ultimately forming insoluble amyloid plaques (also termed senile plaques) present in the diseased brain (Hampel et al., 2021). This global minimum energy peptide assembly is stabilized by backbone-to-backbone in-register hydrogen bonding of peptides in the β-strand conformation. The tertiary structure of amyloid fibrils is biophysically described as β-strands perpendicular to the fibrillar axis and exhibiting the characteristic cross-β X-ray diffraction pattern (Nirmalraj et al., 2020). Quaternary structures include soluble oligomers, higher-order structures that form colloids, and yet higher-order insoluble plaque (Figure 1). Each order of amyloid aggregation is bound to exhibit its own pathological (or as more recently emergent, physiological) relevance. Factors influencing the propensity of amyloid conformation include the identity of residues, local environment, concentration, and local primary structure. The residues Arg and particularly Lys have a low β-strand propensity. Their covalent modification at the side-chain amino or guanidyl functions increases hydrophobicity—one of the promoters of the β-strand conformation. Related Articles | Metrics

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Advances in non-invasive imaging of proteinopathies in animal models of neurodegenerative diseases Lei Cao, Bin Ji, Ruiqing Ni 2024, 19 (10):  2115-2116.  doi: 10.4103/1673-5374.392886 Abstract ( 89 )   PDF (3697KB) ( 44 )   Save Neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal dementia, Parkinson’s disease, and dementia with Lewy bodies, represent tremendous unmet clinical needs. A common feature of these diseases is the aberrant cerebral accumulation of pathological protein aggregates, affecting selectively vulnerable circuits in a disease-specific pattern. Earlier studies have established a relationship between abnormal aggregation and neuronal dysfunction or loss, suggesting multifactorial pathogenesis mechanisms in these neurodegenerative disorders. Developing disease-modifying drugs requires a thorough molecular understanding of how the proteinopathies progressively spread and the link to neurodegeneration and cognitive impairment. Preventing and removing pathological protein aggregates has shown potential as an effective therapeutic strategy for these proteinopathies. Immunotherapies have demonstrated slowing the rate of cognitive decline by effectively removing pathological amyloid-beta (Aβ) deposits in patients with AD. Several immunotherapeutic approaches targeting tau, alpha-synuclein, and TAR DNA-binding protein 43 for the treatment of neurodegenerative disorders, including AD, primary tauopathies, alpha-synucleinopathies, and amyotrophic lateral sclerosis, are currently in clinical trials. Advances in neuroimaging technology have enabled the noninvasive detection of physiopathological events in the brains of living patients and disease animal models. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) with radioactive ligands for protein aggregates such as Aβ, tau, and alpha-synuclein with β-sheet structures have facilitated the early and differential detection of AD and primary tauopathies. Aβ and tau PET have demonstrated their clinical utility and validity and are considered surrogate efficacy endpoints in clinical trials of pharmacological or emerging nonpharmacological treatments. In the era of disease-modifying therapy, imaging biomarkers are expected to play an increasingly important role in early diagnosis, patient stratification, and monitoring, in addition to fluid biomarkers. Related Articles | Metrics

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Status of biomarker development for frontotemporal dementia and amyotrophic lateral sclerosis Yue Yang, Qi Cheng, Jianqun Gao, Woojin Scott Kim 2024, 19 (10):  2117-2118.  doi: 10.4103/1673-5374.392883 Abstract ( 103 )   PDF (487KB) ( 56 )   Save Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that belong to the same disease spectrum, with overlapping of genetic and pathological features. Genetic mutations in TARDBP, C9ORF72, MAPT, and GRN have been identified in these diseases. The TARDBP gene encodes transactive response DNA binding protein 43 kDa (TDP-43), and abnormal deposition of TDP-43 is present in approximately 50% of FTD and 95% of ALS (Neumann et al., 2006). It is present as native TDP-43, phosphorylated TDP-43 (pTDP-43), and other truncated forms. C9ORF72 is the most common genetic abnormality implicated in behavioral-variant FTD (bvFTD), and in approximately 40% of familial ALS. The number of C9ORF72 G4C2 hexanucleotide repeats in healthy individuals is approximately 2–20, whereas in bvFTD and ALS hundreds or thousands. The second most common pathological protein aggregation in FTD is the MAPT gene product tau. Over 50 MAPT mutations have been identified in FTD. Abnormal accumulation of SOD1 is the second most common pathology in ALS, and a number of SOD1 mutations have been identified in ALS. Heterozygous mutations in GRN lead to autosomal-dominant FTD, which is associated with TDP-43 deposits, as well as other pathologies. Similar pathologies resulting from these mutations, as well as similar or overlapping clinical features between the two diseases and their subtypes, underscore the importance of developing biomarkers for FTD and ALS. Peripheral biomarkers would flag cases at the pre-symptomatic stage, facilitate more accurate diagnosis and differential diagnosis of diseases or disease subtypes, predict the progression and prognosis of diseases, and monitor the effects of therapeutic interventions (Figure 1). At present, there are no definitive biomarkers that serve these purposes in FTD and ALS. However, recent progress in biomarker development has identified candidates with improved biomarker potential. Related Articles | Metrics

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Connecting cellular mechanisms and extracellular vesicle cargo in traumatic brain injury Nikita Ollen-Bittle, Austyn D. Roseborough, Wenxuan Wang, Jeng-liang D. Wu, Shawn N. Whitehead 2024, 19 (10):  2119-2131.  doi: 10.4103/1673-5374.391329 Abstract ( 108 )   PDF (919KB) ( 59 )   Save Traumatic brain injury is followed by a cascade of dynamic and complex events occurring at the cellular level. These events include: diffuse axonal injury, neuronal cell death, blood-brain barrier break down, glial activation and neuroinflammation, edema, ischemia, vascular injury, energy failure, and peripheral immune cell infiltration. The timing of these events post injury has been linked to injury severity and functional outcome. Extracellular vesicles are membrane bound secretory vesicles that contain markers and cargo pertaining to their cell of origin and can cross the blood-brain barrier. These qualities make extracellular vesicles intriguing candidates for a liquid biopsy into the pathophysiologic changes occurring at the cellular level post traumatic brain injury. Herein, we review the most commonly reported cargo changes in extracellular vesicles from clinical traumatic brain injury samples. We then use knowledge from animal and in vitro models to help infer what these changes may indicate regrading cellular responses post traumatic brain injury. Future research should prioritize labeling extracellular vesicles with markers for distinct cell types across a range of timepoints post traumatic brain injury. Related Articles | Metrics

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Oligodendrocytes in central nervous system diseases: the effect of cytokine regulation Chengfu Zhang, Mengsheng Qiu, Hui Fu 2024, 19 (10):  2132-2143.  doi: 10.4103/1673-5374.392854 Abstract ( 320 )   PDF (1210KB) ( 96 )   Save Cytokines including tumor necrosis factor, interleukins, interferons, and chemokines are abundantly produced in various diseases. As pleiotropic factors, cytokines are involved in nearly every aspect of cellular functions such as migration, survival, proliferation, and differentiation. Oligodendrocytes are the myelin-forming cells in the central nervous system and play critical roles in the conduction of action potentials, supply of metabolic components for axons, and other functions. Emerging evidence suggests that both oligodendrocytes and oligodendrocyte precursor cells are vulnerable to cytokines released under pathological conditions. This review mainly summarizes the effects of cytokines on oligodendrocyte lineage cells in central nervous system diseases. A comprehensive understanding of the effects of cytokines on oligodendrocyte lineage cells contributes to our understanding of central nervous system diseases and offers insights into treatment strategies. Related Articles | Metrics

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Potential role of hippocampal neurogenesis in spinal cord injury induced post-trauma depression Ying Ma, Yue Qiao, Xiang Gao 2024, 19 (10):  2144-2156.  doi: 10.4103/1673-5374.392855 Abstract ( 95 )   PDF (1268KB) ( 59 )   Save It has been reported both in clinic and rodent models that beyond spinal cord injury directly induced symptoms, such as paralysis, neuropathic pain, bladder/bowel dysfunction, and loss of sexual function, there are a variety of secondary complications, including memory loss, cognitive decline, depression, and Alzheimer’s disease. The large-scale longitudinal population-based studies indicate that post-trauma depression is highly prevalent in spinal cord injury patients. Yet, few basic studies have been conducted to address the potential molecular mechanisms. One of possible factors underlying the depression is the reduction of adult hippocampal neurogenesis which may come from less physical activity, social isolation, chronic pain, and elevated neuroinflammation after spinal cord injury. However, there is no clear consensus yet. In this review, we will first summarize the alteration of hippocampal neurogenesis post-spinal cord injury. Then, we will discuss possible mechanisms underlie this important spinal cord injury consequence. Finally, we will outline the potential therapeutic options aimed at enhancing hippocampal neurogenesis to ameliorate depression. Related Articles | Metrics

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Biomaterials and tissue engineering in traumatic brain injury: novel perspectives on promoting neural regeneration Shihong Zhu, Xiaoyin Liu, Xiyue Lu, Qiang Liao, Huiyang Luo, Yuan Tian, Xu Cheng, Yaxin Jiang, Guangdi Liu, Jing Chen 2024, 19 (10):  2157-2174.  doi: 10.4103/1673-5374.391179 Abstract ( 253 )   PDF (7185KB) ( 136 )   Save Traumatic brain injury is a serious medical condition that can be attributed to falls, motor vehicle accidents, sports injuries and acts of violence, causing a series of neural injuries and neuropsychiatric symptoms. However, limited accessibility to the injury sites, complicated histological and anatomical structure, intricate cellular and extracellular milieu, lack of regenerative capacity in the native cells, vast variety of damage routes, and the insufficient time available for treatment have restricted the widespread application of several therapeutic methods in cases of central nervous system injury. Tissue engineering and regenerative medicine have emerged as innovative approaches in the field of nerve regeneration. By combining biomaterials, stem cells, and growth factors, these approaches have provided a platform for developing effective treatments for neural injuries, which can offer the potential to restore neural function, improve patient outcomes, and reduce the need for drugs and invasive surgical procedures. Biomaterials have shown advantages in promoting neural development, inhibiting glial scar formation, and providing a suitable biomimetic neural microenvironment, which makes their application promising in the field of neural regeneration. For instance, bioactive scaffolds loaded with stem cells can provide a biocompatible and biodegradable milieu. Furthermore, stem cells-derived exosomes combine the advantages of stem cells, avoid the risk of immune rejection, cooperate with biomaterials to enhance their biological functions, and exert stable functions, thereby inducing angiogenesis and neural regeneration in patients with traumatic brain injury and promoting the recovery of brain function. Unfortunately, biomaterials have shown positive effects in the laboratory, but when similar materials are used in clinical studies of human central nervous system regeneration, their efficacy is unsatisfactory. Here, we review the characteristics and properties of various bioactive materials, followed by the introduction of applications based on biochemistry and cell molecules, and discuss the emerging role of biomaterials in promoting neural regeneration. Further, we summarize the adaptive biomaterials infused with exosomes produced from stem cells and stem cells themselves for the treatment of traumatic brain injury. Finally, we present the main limitations of biomaterials for the treatment of traumatic brain injury and offer insights into their future potential. Related Articles | Metrics

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Efficacy of exercise rehabilitation for managing patients with Alzheimer’s disease Dan Li, Jinning Jia, Haibo Zeng, Xiaoyan Zhong, Hui Chen, Chenju Yi 2024, 19 (10):  2175-2188.  doi: 10.4103/1673-5374.391308 Abstract ( 200 )   PDF (1518KB) ( 100 )   Save Alzheimer’s disease (AD) is a progressive and degenerative neurological disease characterized by the deterioration of cognitive functions. While a definitive cure and optimal medication to impede disease progression are currently unavailable, a plethora of studies have highlighted the potential advantages of exercise rehabilitation for managing this condition. Those studies show that exercise rehabilitation can enhance cognitive function and improve the quality of life for individuals affected by AD. Therefore, exercise rehabilitation has been regarded as one of the most important strategies for managing patients with AD. Herein, we provide a comprehensive analysis of the currently available findings on exercise rehabilitation in patients with AD, with a focus on the exercise types which have shown efficacy when implemented alone or combined with other treatment methods, as well as the potential mechanisms underlying these positive effects. Specifically, we explain how exercise may improve the brain microenvironment and neuronal plasticity. In conclusion, exercise is a cost-effective intervention to enhance cognitive performance and improve quality of life in patients with mild to moderate cognitive dysfunction. Therefore, it can potentially become both a physical activity and a tailored intervention. This review may aid the development of more effective and individualized treatment strategies to address the challenges imposed by this debilitating disease, especially in low- and middle-income countries. Related Articles | Metrics

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Metabolic reprogramming of the inflammatory response in the nervous system: the crossover between inflammation and metabolism Jesus Amo-Aparicio, Charles A. Dinarello, Ruben Lopez-Vales 2024, 19 (10):  2189-2201.  doi: 10.4103/1673-5374.391330 Abstract ( 306 )   PDF (2834KB) ( 156 )   Save Metabolism is a fundamental process by which biochemicals are broken down to produce energy (catabolism) or used to build macromolecules (anabolism). Metabolism has received renewed attention as a mechanism that generates molecules that modulate multiple cellular responses. This was first identified in cancer cells as the Warburg effect, but it is also present in immunocompetent cells. Studies have revealed a bidirectional influence of cellular metabolism and immune cell function, highlighting the significance of metabolic reprogramming in immune cell activation and effector functions. Metabolic processes such as glycolysis, oxidative phosphorylation, and fatty acid oxidation have been shown to undergo dynamic changes during immune cell response, facilitating the energetic and biosynthetic demands. This review aims to provide a better understanding of the metabolic reprogramming that occurs in different immune cells upon activation, with a special focus on central nervous system disorders. Understanding the metabolic changes of the immune response not only provides insights into the fundamental mechanisms that regulate immune cell function but also opens new approaches for therapeutic strategies aimed at manipulating the immune system. Related Articles | Metrics

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Endoplasmic reticulum stress, autophagy, neuroinflammation, and sigma 1 receptors as contributors to depression and its treatment Chika Fujii, Charles F. Zorumski, Yukitoshi Izumi 2024, 19 (10):  2202-2211.  doi: 10.4103/1673-5374.391334 Abstract ( 164 )   PDF (955KB) ( 67 )   Save The etiological factors contributing to depression and other neuropsychiatric disorders are largely undefined. Endoplasmic reticulum stress pathways and autophagy are well-defined mechanisms that play critical functions in recognizing and resolving cellular stress and are possible targets for the pathophysiology and treatment of psychiatric and neurologic illnesses. An increasing number of studies indicate the involvement of endoplasmic reticulum stress and autophagy in the control of neuroinflammation, a contributing factor to multiple neuropsychiatric illnesses. Initial inflammatory triggers induce endoplasmic reticulum stress, leading to neuroinflammatory responses. Subsequently, induction of autophagy by neurosteroids and other signaling pathways that converge on autophagy induction are thought to participate in resolving neuroinflammation. The aim of this review is to summarize our current understanding of the molecular mechanisms governing the induction of endoplasmic reticulum stress, autophagy, and neuroinflammation in the central nervous system. Studies focused on innate immune factors, including neurosteroids with anti-inflammatory roles will be reviewed. In the context of depression, animal models that led to our current understanding of molecular mechanisms underlying depression will be highlighted, including the roles of sigma 1 receptors and pharmacological agents that dampen endoplasmic reticulum stress and associated neuroinflammation. Related Articles | Metrics

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Glyphosate as a direct or indirect activator of pro-inflammatory signaling and cognitive impairment#br# Yukitoshi Izumi, Kazuko A. O’Dell, Charles F. Zorumski 2024, 19 (10):  2212-2218.  doi: 10.4103/1673-5374.391331 Abstract ( 115 )   PDF (606KB) ( 59 )   Save Glyphosate-based herbicides are widely used around the world, making it likely that most humans have significant exposure. Because of habitual exposure, there are concerns about toxicity including neurotoxicity that could result in neurological, psychiatric, or cognitive impairment. We recently found that a single injection of glyphosate inhibits long-term potentiation, a cellular model of learning and memory, in rat hippocampal slices dissected 1 day after injection, indicating that glyphosate-based herbicides can alter cognitive function. Glyphosate-based herbicides could adversely affect cognitive function either indirectly and/or directly. Indirectly, glyphosate could affect gut microbiota, and if dysbiosis results in endotoxemia (leaky gut), infiltrated bacterial by-products such as lipopolysaccharides could activate pro-inflammatory cascades. Glyphosate can also directly trigger pro-inflammatory cascades. Indeed, we observed that acute glyphosate exposure inhibits long-term potentiation in rat hippocampal slices. Interestingly, direct inhibition of long-term potentiation by glyphosate appears to be similar to that of lipopolysaccharides. There are several possible measures to control dysbiosis and neuroinflammation caused by glyphosate. Dietary intake of polyphenols, such as quercetin, which overcome the inhibitory effect of glyphosate on long-term potentiation, could be one effective strategy. The aim of this narrative review is to discuss possible mechanisms underlying neurotoxicity following glyphosate exposure as a means to identify potential treatments. Related Articles | Metrics

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Unraveling the gut-brain axis: the impact of steroid hormones and nutrition on Parkinson’s disease Paula Maria Neufeld, Ralf A. Nettersheim, Veronika Matschke, Matthias Vorgerd, Sarah Stahlke, Carsten Theiss 2024, 19 (10):  2219-2228.  doi: 10.4103/1673-5374.391304 Abstract ( 109 )   PDF (1158KB) ( 96 )   Save This comprehensive review explores the intricate relationship between nutrition, the gut microbiome, steroid hormones, and Parkinson’s disease within the context of the gut-brain axis. The gut-brain axis plays a pivotal role in neurodegenerative diseases like Parkinson’s disease, encompassing diverse components such as the gut microbiota, immune system, metabolism, and neural pathways. The gut microbiome, profoundly influenced by dietary factors, emerges as a key player. Nutrition during the first 1000 days of life shapes the gut microbiota composition, influencing immune responses and impacting both child development and adult health. High-fat, high-sugar diets can disrupt this delicate balance, contributing to inflammation and immune dysfunction. Exploring nutritional strategies, the Mediterranean diet’s anti-inflammatory and antioxidant properties show promise in reducing Parkinson’s disease risk. Microbiome-targeted dietary approaches and the ketogenic diet hold the potential in improving brain disorders. Beyond nutrition, emerging research uncovers potential interactions between steroid hormones, nutrition, and Parkinson’s disease. Progesterone, with its anti-inflammatory properties and presence in the nervous system, offers a novel option for Parkinson’s disease therapy. Its ability to enhance neuroprotection within the enteric nervous system presents exciting prospects. The review addresses the hypothesis that α-synuclein aggregates originate from the gut and may enter the brain via the vagus nerve. Gastrointestinal symptoms preceding motor symptoms support this hypothesis. Dysfunctional gut-brain signaling during gut dysbiosis contributes to inflammation and neurotransmitter imbalances, emphasizing the potential of microbiota-based interventions. In summary, this review uncovers the complex web of interactions between nutrition, the gut microbiome, steroid hormones, and Parkinson’s disease within the gut-brain axis framework. Understanding these connections not only offers novel therapeutic insights but also illuminates the origins of neurodegenerative diseases such as Parkinson’s disease. Related Articles | Metrics

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Association of DNA methylation/demethylation with the functional outcome of stroke in a hyperinflammatory state Yubo Wang, Ling Zhang, Tianjie Lyu, Lu Cui, Shunying Zhao, Xuechun Wang, Meng Wang, Yongjun Wang, Zixiao Li 2024, 19 (10):  2229-2239.  doi: 10.4103/1673-5374.392890 Abstract ( 164 )   PDF (2020KB) ( 100 )   Save Inflammation is closely related to stroke prognosis, and high inflammation status leads to poor functional outcome in stroke. DNA methylation is involved in the pathogenesis and prognosis of stroke. However, the effect of DNA methylation on stroke at high levels of inflammation is unclear. In this study, we constructed a hyperinflammatory cerebral ischemia mouse model and investigated the effect of hypomethylation and hypermethylation on the functional outcome. We constructed a mouse model of transient middle cerebral artery occlusion and treated the mice with lipopolysaccharide to induce a hyperinflammatory state. To investigate the effect of DNA methylation on stroke, we used small molecule inhibitors to restrain the function of key DNA methylation and demethylation enzymes. 2,3,5-Triphenyltetrazolium chloride staining, neurological function scores, neurobehavioral tests, enzyme-linked immunosorbent assay, quantitative reverse transcription PCR and western blot assay were used to evaluate the effects after stroke in mice. We assessed changes in the global methylation status by measuring DNA 5-mc and DNA 5-hmc levels in peripheral blood after the use of the inhibitor. In the group treated with the DNA methylation inhibitor, brain tissue 2,3,5-triphenyltetrazolium chloride staining showed an increase in infarct volume, which was accompanied by a decrease in neurological scores and worsening of neurobehavioral performance. The levels of inflammatory factors interleukin 6 and interleukin-1 beta in ischemic brain tissue and plasma were elevated, indicating increased inflammation. Related inflammatory pathway exploration showed significant overactivation of nuclear factor kappa B. These results suggested that inhibiting DNA methylation led to poor functional outcome in mice with high inflammation following stroke. Further, the effects were reversed by inhibition of DNA demethylation. Our findings suggest that DNA methylation regulates the inflammatory response in stroke and has an important role in the functional outcome of hyperinflammatory stroke. Related Articles | Metrics

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In situ direct reprogramming of astrocytes to neurons via polypyrimidine tract-binding protein 1 knockdown in a mouse model of ischemic stroke Meng Yuan, Yao Tang, Tianwen Huang, Lining Ke, En Huang 2024, 19 (10):  2240-2248.  doi: 10.4103/1673-5374.390957 Abstract ( 149 )   PDF (7848KB) ( 80 )   Save In situ direct reprogramming technology can directly convert endogenous glial cells into functional neurons in vivo for central nervous system repair. Polypyrimidine tract-binding protein 1 (PTB) knockdown has been shown to reprogram astrocytes to functional neurons in situ. In this study, we used AAV-PHP.eB-GFAP-shPTB to knockdown PTB in a mouse model of ischemic stroke induced by endothelin-1, and investigated the effects of GFAP-shPTB-mediated direct reprogramming to neurons. Our results showed that in the mouse model of ischemic stroke, PTB knockdown effectively reprogrammed GFAP-positive cells to neurons in ischemic foci, restored neural tissue structure, reduced inflammatory response, and improved behavioral function. These findings validate the effectiveness of in situ transdifferentiation of astrocytes, and suggest that the approach may be a promising strategy for stroke treatment. Related Articles | Metrics

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Growth hormone promotes the reconstruction of injured axons in the hypothalamo-neurohypophyseal system Kai Li, Zhanpeng Feng, Zhiwei Xiong, Jun Pan, Mingfeng Zhou, Weizhao Li, Yichao Ou, Guangsen Wu, Mengjie Che, Haodong Gong, Junjie Peng, Xingqin Wang, Songtao Qi, Junxiang Peng 2024, 19 (10):  2249-2258.  doi: 10.4103/1673-5374.389358 Abstract ( 149 )   PDF (7951KB) ( 38 )   Save Previous studies have shown that growth hormone can regulate hypothalamic energy metabolism, stress, and hormone release. Therefore, growth hormone has great potential for treating hypothalamic injury. In this study, we established a specific hypothalamic axon injury model by inducing hypothalamic pituitary stalk electric lesions in male mice. We then treated mice by intraperitoneal administration of growth hormone. Our results showed that growth hormone increased the expression of insulin-like growth factor 1 and its receptors, and promoted the survival of hypothalamic neurons, axonal regeneration, and vascular reconstruction from the median eminence through the posterior pituitary. Altogether, this alleviated hypothalamic injury-caused central diabetes insipidus and anxiety. These results suggest that growth hormone can promote axonal reconstruction after hypothalamic injury by regulating the growth hormone-insulin-like growth factor 1 axis. Related Articles | Metrics

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Small extracellular vesicles from hypoxia-preconditioned bone marrow mesenchymal stem cells attenuate spinal cord injury via miR-146a-5p-mediated regulation of macrophage polarization Zeyan Liang, Zhelun Yang, Haishu Xie, Jian Rao, Xiongjie Xu, Yike Lin, Chunhua Wang, Chunmei Chen 2024, 19 (10):  2259-2269.  doi: 10.4103/1673-5374.391194 Abstract ( 130 )   PDF (17835KB) ( 80 )   Save Spinal cord injury is a disabling condition with limited treatment options. Multiple studies have provided evidence suggesting that small extracellular vesicles (SEVs) secreted by bone marrow mesenchymal stem cells (MSCs) help mediate the beneficial effects conferred by MSC transplantation following spinal cord injury. Strikingly, hypoxia-preconditioned bone marrow mesenchymal stem cell-derived SEVs (HSEVs) exhibit increased therapeutic potency. We thus explored the role of HSEVs in macrophage immune regulation after spinal cord injury in rats and their significance in spinal cord repair. SEVs or HSEVs were isolated from bone marrow MSC supernatants by density gradient ultracentrifugation. HSEV administration to rats via tail vein injection after spinal cord injury reduced the lesion area and attenuated spinal cord inflammation. HSEVs regulate macrophage polarization towards the M2 phenotype in vivo and in vitro. MicroRNA sequencing and bioinformatics analyses of SEVs and HSEVs revealed that miR-146a-5p is a potent mediator of macrophage polarization that targets interleukin-1 receptor-associated kinase 1. Reducing miR-146a-5p expression in HSEVs partially attenuated macrophage polarization. Our data suggest that HSEVs attenuate spinal cord inflammation and injury in rats by transporting miR-146a-5p, which alters macrophage polarization. This study provides new insights into the application of HSEVs as a therapeutic tool for spinal cord injury. Related Articles | Metrics

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3′-Deoxyadenosin alleviates methamphetamine-induced aberrant synaptic plasticity and seeking behavior by inhibiting the NLRP3 inflammasome Yize Qi, Yao Zhou, Jiyang Li, Fangyuan Zhu, Gengni Guo, Can Wang, Man Yu, Yijie Wang, Tengfei Ma, Shanwu Feng, Li Zhou 2024, 19 (10):  2270-2280.  doi: 10.4103/1673-5374.392887 Abstract ( 131 )   PDF (1952KB) ( 76 )   Save Methamphetamine addiction is a brain disorder characterized by persistent drug-seeking behavior, which has been linked with aberrant synaptic plasticity. An increasing body of evidence suggests that aberrant synaptic plasticity is associated with the activation of the NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasome. 3′-Deoxyadenosin, an active component of the Chinese fungus Cordyceps militaris, has strong anti-inflammatory effects. However, whether 3′-deoxyadenosin attenuates methamphetamine-induced aberrant synaptic plasticity via an NLRP3-mediated inflammatory mechanism remains unclear. We first observed that 3′-deoxyadenosin attenuated conditioned place preference scores in methamphetamine-treated mice and decreased the expression of c-fos in hippocampal neurons. Furthermore, we found that 3′-deoxyadenosin reduced the aberrant potentiation of glutamatergic transmission and restored the methamphetamine-induced impairment of synaptic plasticity. We also found that 3′-deoxyadenosin decreased the expression of NLRP3 and neuronal injury. Importantly, a direct NLRP3 deficiency reduced methamphetamine-induced seeking behavior, attenuated the impaired synaptic plasticity, and prevented neuronal damage. Finally, NLRP3 activation reversed the effect of 3′-deoxyadenosin on behavior and synaptic plasticity, suggesting that the anti-neuroinflammatory mechanism of 3′-deoxyadenosin on aberrant synaptic plasticity reduces methamphetamine-induced seeking behavior. Taken together, 3′-deoxyadenosin alleviates methamphetamine-induced aberrant synaptic plasticity and seeking behavior by inhibiting the NLRP3 inflammasome. Related Articles | Metrics

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Magnesium-L-threonate treats Alzheimer’s disease by modulating the microbiota-gut-brain axis Wang Liao, Jiana Wei, Chongxu Liu, Haoyu Luo, Yuting Ruan, Yingren Mai, Qun Yu, Zhiyu Cao, Jiaxin Xu, Dong Zheng, Zonghai Sheng, Xianju Zhou, Jun Liu 2024, 19 (10):  2281-2289.  doi: 10.4103/1673-5374.391310 Abstract ( 198 )   PDF (6201KB) ( 70 )   Save Disturbances in the microbiota-gut-brain axis may contribute to the development of Alzheimer’s disease. Magnesium-L-threonate has recently been found to have protective effects on learning and memory in aged and Alzheimer’s disease model mice. However, the effects of magnesium-L-threonate on the gut microbiota in Alzheimer’s disease remain unknown. Previously, we reported that magnesium-L-threonate treatment improved cognition and reduced oxidative stress and inflammation in a double-transgenic line of Alzheimer’s disease model mice expressing the amyloid-β precursor protein and mutant human presenilin 1 (APP/PS1). Here, we performed 16S rRNA amplicon sequencing and liquid chromatography-mass spectrometry to analyze changes in the microbiome and serum metabolome following magnesium-L-threonate exposure in a similar mouse model. Magnesium-L-threonate modulated the abundance of three genera in the gut microbiota, decreasing Allobaculum and increasing Bifidobacterium and Turicibacter. We also found that differential metabolites in the magnesium-L-threonate-regulated serum were enriched in various pathways associated with neurodegenerative diseases. The western blotting detection on intestinal tight junction proteins (zona occludens 1, occludin, and claudin-5) showed that magnesium-L-threonate repaired the intestinal barrier dysfunction of APP/PS1 mice. These findings suggest that magnesium-L-threonate may reduce the clinical manifestations of Alzheimer’s disease through the microbiota-gut-brain axis in model mice, providing an experimental basis for the clinical treatment of Alzheimer’s disease. Related Articles | Metrics

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Lycium barbarum glycopeptide (wolfberry extract) slows N-methyl-N-nitrosourea-induced degradation of photoreceptors Qihang Kong, Xiu Han, Haiyang Cheng, Jiayu Liu, Huijun Zhang, Tangrong Dong, Jiansu Chen, Kwok-Fai So, Xuesong Mi, Ying Xu, Shibo Tang 2024, 19 (10):  2290-2298.  doi: 10.4103/1673-5374.390958 Abstract ( 183 )   PDF (2609KB) ( 76 )   Save Photoreceptor cell degeneration leads to blindness, for which there is currently no effective treatment. Our previous studies have shown that Lycium barbarum (L. barbarum) polysaccharide (LBP) protects degenerated photoreceptors in rd1, a transgenic mouse model of retinitis pigmentosa. L. barbarum glycopeptide (LbGP) is an immunoreactive glycoprotein extracted from LBP. In this study, we investigated the potential protective effect of LbGP on a chemically induced photoreceptor-degenerative mouse model. Wild-type mice received the following: oral administration of LbGP as a protective pre-treatment on days 1–7; intraperitoneal administration of 40 mg/kg N-methyl-N-nitrosourea to induce photoreceptor injury on day 7; and continuation of orally administered LbGP on days 8–14. Treatment with LbGP increased photoreceptor survival and improved the structure of photoreceptors, retinal photoresponse, and visual behaviors of mice with photoreceptor degeneration. LbGP was also found to partially inhibit the activation of microglia in N-methyl-N-nitrosourea-injured retinas and significantly decreased the expression of two pro-inflammatory cytokines. In conclusion, LbGP effectively slowed the rate of photoreceptor degeneration in N-methyl-N-nitrosourea-injured mice, possibly through an anti-inflammatory mechanism, and has potential as a candidate drug for the clinical treatment of photoreceptor degeneration. Related Articles | Metrics

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p38 MAPK inhibitor SB202190 suppresses ferroptosis in the glutamate-induced retinal excitotoxicity glaucoma model Lemeng Feng, Chao Wang, Cheng Zhang, Wulong Zhang, Weiming Zhu, Ye He, Zhaohua Xia, Weitao Song 2024, 19 (10):  2299-2309.  doi: 10.4103/1673-5374.391193 Abstract ( 141 )   PDF (7235KB) ( 54 )   Save Glutamate excitotoxicity has been shown to play an important role in glaucoma, and glutamate can induce ferroptosis. The p38 mitogen-activated protein kinase (MAPK) pathway inhibitor SB202190 has a potential ability to suppress ferroptosis, and its downstream targets, such as p53, have been shown to be associated with ferroptosis. However, whether ferroptosis also occurs in retinal ganglion cells in response to glutamate excitotoxicity and whether inhibition of ferroptosis reduces the loss of retinal ganglion cells induced by glutamate excitotoxicity remain unclear. This study investigated ferroptosis in a glutamate-induced glaucoma rat model and explored the effects and molecular mechanisms of SB202190 on retinal ganglion cells. A glutamate-induced excitotoxicity model in R28 cells and an N-methyl-D-aspartate-induced glaucoma model in rats were used. In vitro experiments showed that glutamate induced the accumulation of iron and lipid peroxide and morphological changes of mitochondria in R28 cells, and SB202190 inhibited these changes. Glutamate induced the levels of p-p38 MAPK/p38 MAPK and SAT1 and decreased the expression levels of ferritin light chain, SLC7A11, and GPX4. SB202190 inhibited the expression of iron death-related proteins induced by glutamate. In vivo experiments showed that SB202190 attenuated N-methyl-D-aspartate-induced damage to rat retinal ganglion cells and improved visual function. These results suggest that SB202190 can inhibit ferroptosis and protect retinal ganglion cells by regulating ferritin light chain, SAT1, and SLC7A11/Gpx4 pathways and may represent a potential retina protectant. Related Articles | Metrics

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Global trends in diabetic eye disease research from 2012 to 2021 Yuan Yuan, Shangli Ji, Yali Song, Zhaodi Che, Lu Xiao, Shibo Tang, Jia Xiao 2024, 19 (10):  2310-2320.  doi: 10.4103/1673-5374.391303 Abstract ( 212 )   PDF (8252KB) ( 59 )   Save Diabetic eye disease refers to a group of eye complications that occur in diabetic patients and include diabetic retinopathy, diabetic macular edema, diabetic cataracts, and diabetic glaucoma. However, the global epidemiology of these conditions has not been well characterized. In this study, we collected information on diabetic eye disease-related research grants from seven representative countries––the United States, China, Japan, the United Kingdom, Spain, Germany, and France––by searching for all global diabetic eye disease journal articles in the Web of Science and PubMed databases, all global registered clinical trials in the ClinicalTrials database, and new drugs approved by the United States, China, Japan, and EU agencies from 2012 to 2021. During this time period, diabetic retinopathy accounted for the vast majority (89.53%) of the 2288 government research grants that were funded to investigate diabetic eye disease, followed by diabetic macular edema (9.27%). The United States granted the most research funding for diabetic eye disease out of the seven countries assessed. The research objectives of grants focusing on diabetic retinopathy and diabetic macular edema differed by country. Additionally, the United States was dominant in terms of research output, publishing 17.53% of global papers about diabetic eye disease and receiving 22.58% of total citations. The United States and the United Kingdom led international collaborations in research into diabetic eye disease. Of the 415 clinical trials that we identified, diabetic macular edema was the major disease that was targeted for drug development (58.19%). Approximately half of the trials (49.13%) pertained to angiogenesis. However, few drugs were approved for ophthalmic (40 out of 1830; 2.19%) and diabetic eye disease (3 out of 1830; 0.02%) applications. Our findings show that basic and translational research related to diabetic eye disease in the past decade has not been highly active, and has yielded few new treatment methods and newly approved drugs. Related Articles | Metrics