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Table of Content

    15 January 2024, Volume 19 Issue 1 Previous Issue   
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    Adult neurogenesis: a real hope or a delusion?
    Ghulam Hussain, Rabia Akram, Haseeb Anwar, Faiqa Sajid, Tehreem Iman, Hyung Soo Han, Chand Raza, Jose-Luis Gonzalez De Aguilar
    2024, 19 (1):  6-15.  doi: 10.4103/1673-5374.375317
    Abstract ( 138 )   PDF (1441KB) ( 164 )   Save
    Adult neurogenesis, the process of creating new neurons, involves the coordinated division, migration, and differentiation of neural stem cells. This process is restricted to neurogenic niches located in two distinct areas of the brain: the subgranular zone of the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricle, where new neurons are generated and then migrate to the olfactory bulb. Neurogenesis has been thought to occur only during the embryonic and early postnatal stages and to decline with age due to a continuous depletion of neural stem cells. Interestingly, recent years have seen tremendous progress in our understanding of adult brain neurogenesis, bridging the knowledge gap between embryonic and adult neurogenesis. Here, we discuss the current status of adult brain neurogenesis in light of what we know about neural stem cells. In this notion, we talk about the importance of intracellular signaling molecules in mobilizing endogenous neural stem cell proliferation. Based on the current understanding, we can declare that these molecules play a role in targeting neurogenesis in the mature brain. However, to achieve this goal, we need to avoid the undesired proliferation of neural stem cells by controlling the necessary checkpoints, which can lead to tumorigenesis and prove to be a curse instead of a blessing or hope.
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    Type-B monoamine oxidase inhibitors in neurological diseases: clinical applications based on preclinical findings
    Marika Alborghetti, Edoardo Bianchini, Lanfranco De Carolis, Silvia Galli, Francesco E. Pontieri, Domiziana Rinaldi
    2024, 19 (1):  16-21.  doi: 10.4103/1673-5374.375299
    Abstract ( 174 )   PDF (457KB) ( 169 )   Save
    Type-B monoamine oxidase inhibitors, encompassing selegiline, rasagiline, and safinamide, are available to treat Parkinson’s disease. These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease. There is also evidence supporting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson’s disease, such as mood deflection, cognitive impairment, sleep disturbances, and fatigue. Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson’s disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors, particularly glial cell line-derived neurotrophic factor, which support dopaminergic neurons. Besides, safinamide may interfere with neurodegenerative mechanisms, counteracting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity. Due to the dual mechanism of action, the new generation of type-B monoamine oxidase inhibitors, including safinamide, is gaining interest in other neurological pathologies, and many supporting preclinical studies are now available. The potential fields of application concern epilepsy, Duchenne muscular dystrophy, multiple sclerosis, and above all, ischemic brain injury. The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline, rasagiline, and safinamide in Parkinson’s disease and beyond, focusing on possible future therapeutic applications.
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    The future of artificial hibernation medicine: protection of nerves and organs after spinal cord injury
    Caiyun Liu, Haixin Yu, Zhengchao Li, Shulian Chen, Xiaoyin Li, Xuyi Chen, Bo Chen
    2024, 19 (1):  22-28.  doi: 10.4103/1673-5374.375305
    Abstract ( 337 )   PDF (583KB) ( 161 )   Save
    Spinal cord injury is a serious disease of the central nervous system involving irreversible nerve injury and various organ system injuries. At present, no effective clinical treatment exists. As one of the artificial hibernation techniques, mild hypothermia has preliminarily confirmed its clinical effect on spinal cord injury. However, its technical defects and barriers, along with serious clinical side effects, restrict its clinical application for spinal cord injury. Artificial hibernation is a future-oriented disruptive technology for human life support. It involves endogenous hibernation inducers and hibernation-related central neuromodulation that activate particular neurons, reduce the central constant temperature setting point, disrupt the normal constant body temperature, make the body “adapt” to the external cold environment, and reduce the physiological resistance to cold stimulation. Thus, studying the artificial hibernation mechanism may help develop new treatment strategies more suitable for clinical use than the cooling method of mild hypothermia technology. This review introduces artificial hibernation technologies, including mild hypothermia technology, hibernation inducers, and hibernation-related central neuromodulation technology. It summarizes the relevant research on hypothermia and hibernation for organ and nerve protection. These studies show that artificial hibernation technologies have therapeutic significance on nerve injury after spinal cord injury through inflammatory inhibition, immunosuppression, oxidative defense, and possible central protection. It also promotes the repair and protection of respiratory and digestive, cardiovascular, locomotor, urinary, and endocrine systems. This review provides new insights for the clinical treatment of nerve and multiple organ protection after spinal cord injury thanks to artificial hibernation. At present, artificial hibernation technology is not mature, and research faces various challenges. Nevertheless, the effort is worthwhile for the future development of medicine.
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    Are TrkB receptor agonists the right tool to fulfill the promises for a therapeutic value of the brain-derived neurotrophic factor?
    Marta Zagrebelsky, Martin Korte
    2024, 19 (1):  29-34.  doi: 10.4103/1673-5374.374138
    Abstract ( 147 )   PDF (1228KB) ( 105 )   Save
    Brain-derived neurotrophic factor signaling via its receptor tropomyosin receptor kinase B regulates several crucial physiological processes. It has been shown to act in the brain, promoting neuronal survival, growth, and plasticity as well as in the rest of the body where it is involved in regulating for instance aspects of the metabolism. Due to its crucial and very pleiotropic activity, reduction of brain-derived neurotrophic factor levels and alterations in the brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling have been found to be associated with a wide spectrum of neurological diseases. However, because of its poor bioavailability and pharmacological properties, brain-derived neurotrophic factor itself has a very low therapeutic value. Moreover, the concomitant binding of exogenous brain-derived neurotrophic factor to the p75 neurotrophin receptor has the potential to elicit several unwanted and deleterious side effects. Therefore, developing tools and approaches to specifically promote tropomyosin receptor kinase B signaling has become an important goal of translational research. Among the newly developed tools are different categories of tropomyosin receptor kinase B receptor agonist molecules. In this review, we give a comprehensive description of the different tropomyosin receptor kinase B receptor agonist drugs developed so far and of the results of their application in animal models of several neurological diseases. Moreover, we discuss the main benefits of tropomyosin receptor kinase B receptor agonists, concentrating especially on the new tropomyosin receptor kinase B agonist antibodies. The benefits observed both in vitro and in vivo upon application of tropomyosin receptor kinase B receptor agonist drugs seem to predominantly depend on their general neuroprotective activity and their ability to promote neuronal plasticity. Moreover, tropomyosin receptor kinase B agonist antibodies have been shown to specifically bind the tropomyosin receptor kinase B receptor and not p75 neurotrophin receptor. Therefore, while, based on the current knowledge, the tropomyosin receptor kinase B receptor agonists do not seem to have the potential to reverse the disease pathology per se, promoting brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling still has a very high therapeutic relevance.
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    Pharmacological interventions targeting the microcirculation following traumatic spinal cord injury
    Rongrong Wang, Jinzhu Bai
    2024, 19 (1):  35-42.  doi: 10.4103/1673-5374.375304
    Abstract ( 317 )   PDF (1014KB) ( 162 )   Save
    Traumatic spinal cord injury is a devastating disorder characterized by sensory, motor, and autonomic dysfunction that severely compromises an individual’s ability to perform activities of daily living. These adverse outcomes are closely related to the complex mechanism of spinal cord injury, the limited regenerative capacity of central neurons, and the inhibitory environment formed by traumatic injury. Disruption to the microcirculation is an important pathophysiological mechanism of spinal cord injury. A number of therapeutic agents have been shown to improve the injury environment, mitigate secondary damage, and/or promote regeneration and repair. Among them, the spinal cord microcirculation has become an important target for the treatment of spinal cord injury. Drug interventions targeting the microcirculation can improve the microenvironment and promote recovery following spinal cord injury. These drugs target the structure and function of the spinal cord microcirculation and are essential for maintaining the normal function of spinal neurons, axons, and glial cells. This review discusses the pathophysiological role of spinal cord microcirculation in spinal cord injury, including its structure and histopathological changes. Further, it summarizes the progress of drug therapies targeting the spinal cord microcirculation after spinal cord injury.
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    Metabolic and proteostatic differences in quiescent and active neural stem cells
    Jiacheng Yu, Gang Chen, Hua Zhu, Yi Zhong, Zhenxing Yang, Zhihong Jian, Xiaoxing Xiong
    2024, 19 (1):  43-48.  doi: 10.4103/1673-5374.375306
    Abstract ( 345 )   PDF (1526KB) ( 205 )   Save
    Adult neural stem cells are neurogenesis progenitor cells that play an important role in neurogenesis. Therefore, neural regeneration may be a promising target for treatment of many neurological illnesses. The regenerative capacity of adult neural stem cells can be characterized by two states: quiescent and active. Quiescent adult neural stem cells are more stable and guarantee the quantity and quality of the adult neural stem cell pool. Active adult neural stem cells are characterized by rapid proliferation and differentiation into neurons which allow for integration into neural circuits. This review focuses on differences between quiescent and active adult neural stem cells in nutrition metabolism and protein homeostasis. Furthermore, we discuss the physiological significance and underlying advantages of these differences. Due to the limited number of adult neural stem cells studies, we referred to studies of embryonic adult neural stem cells or non-mammalian adult neural stem cells to evaluate specific mechanisms.
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    Mesenchymal stem cell-derived extracellular vesicles as a cell-free therapy for traumatic brain injury via neuroprotection and neurorestoration
    Ye Xiong, Asim Mahmood, Michael Chopp
    2024, 19 (1):  49-54.  doi: 10.4103/1673-5374.374143
    Abstract ( 216 )   PDF (645KB) ( 97 )   Save
    Traumatic brain injury is a serious and complex neurological condition that affects millions of people worldwide. Despite significant advancements in the field of medicine, effective treatments for traumatic brain injury remain limited. Recently, extracellular vesicles released from mesenchymal stem/stromal cells have emerged as a promising novel therapy for traumatic brain injury. Extracellular vesicles are small membrane-bound vesicles that are naturally released by cells, including those in the brain, and can be engineered to contain therapeutic cargo, such as anti-inflammatory molecules, growth factors, and microRNAs. When administered intravenously, extracellular vesicles can cross the blood-brain barrier and deliver their cargos to the site of injury, where they can be taken up by recipient cells and modulate the inflammatory response, promote neuroregeneration, and improve functional outcomes. In preclinical studies, extracellular vesicle-based therapies have shown promising results in promoting recovery after traumatic brain injury, including reducing neuronal damage, improving cognitive function, and enhancing motor recovery. While further research is needed to establish the safety and efficacy of extracellular vesicle-based therapies in humans, extracellular vesicles represent a promising novel approach for the treatment of traumatic brain injury. In this review, we summarize mesenchymal stem/stromal cell-derived extracellular vesicles as a cell-free therapy for traumatic brain injury via neuroprotection and neurorestoration and brain-derived extracellular vesicles as potential biofluid biomarkers in small and large animal models of traumatic brain injury.
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    Pathological and therapeutic effects of extracellular vesicles in neurological and neurodegenerative diseases
    Paula Izquierdo-Altarejos, Victoria Moreno-Manzano, Vicente Felipo
    2024, 19 (1):  55-61.  doi: 10.4103/1673-5374.375301
    Abstract ( 262 )   PDF (675KB) ( 147 )   Save
    Extracellular vesicles are released by all cell types and contain proteins, microRNAs, mRNAs, and other bioactive molecules. Extracellular vesicles play an important role in intercellular communication and in the modulation of the immune system and neuroinflammation. The cargo of extracellular vesicles (e.g., proteins and microRNAs) is altered in pathological situations. Extracellular vesicles contribute to the pathogenesis of many pathologies associated with sustained inflammation and neuroinflammation, including cancer, diabetes, hyperammonemia and hepatic encephalopathy, and other neurological and neurodegenerative diseases. Extracellular vesicles may cross the blood-brain barrier and transfer pathological signals from the periphery to the brain. This contributes to inducing neuroinflammation and cognitive and motor impairment in hyperammonemia and hepatic encephalopathy and in neurodegenerative diseases. The mechanisms involved are beginning to be understood. For example, increased tumor necrosis factor α in extracellular vesicles from plasma of hyperammonemic rats induces neuroinflammation and motor impairment when injected into normal rats. Identifying the mechanisms by which extracellular vesicles contribute to the pathogenesis of these diseases will help to develop new treatments and diagnostic tools for their easy and early detection. In contrast, extracellular vesicles from mesenchymal stem cells have therapeutic utility in many of the above pathologies, by reducing inflammation and neuroinflammation and improving cognitive and motor function. These extracellular vesicles recapitulate the beneficial effects of mesenchymal stem cells and have advantages as therapeutic tools: they are less immunogenic, may not differentiate to malignant cells, cross the blood-brain barrier, and may reach more easily target organs. Extracellular vesicles from mesenchymal stem cells have beneficial effects in models of ischemic brain injury, Alzheimer’s and Parkinson’s diseases, hyperammonemia, and hepatic encephalopathy. Extracellular vesicles from mesenchymal stem cells modulate the immune system, promoting the shift from a pro-inflammatory to an anti-inflammatory state. For example, extracellular vesicles from mesenchymal stem cells modulate the Th17/Treg balance, promoting the anti-inflammatory Treg. Extracellular vesicles from mesenchymal stem cells may also act directly in the brain to modulate microglia activation, promoting a shift from a pro-inflammatory to an anti-inflammatory state. This reduces neuroinflammation and improves cognitive and motor function. Two main components of extracellular vesicles from mesenchymal stem cells which contribute to these beneficial effects are transforming growth factor-β and miR-124. Identifying the mechanisms by which extracellular vesicles from mesenchymal stem cells induce the beneficial effects and the main molecules (e.g., proteins and mRNAs) involved may help to improve their therapeutic utility. The aims of this review are to summarize the knowledge of the pathological effects of extracellular vesicles in different pathologies, the therapeutic potential of extracellular vesicles from mesenchymal stem cells to recover cognitive and motor function and the molecular mechanisms for these beneficial effects on neurological function.
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    Emergence of taurine as a therapeutic agent for neurological disorders
    Ashok Jangra, Priyanka Gola, Jiten Singh, Pooja Gond, Swarnabha Ghosh, Mahesh Rachamalla, Abhijit Dey, Danish Iqbal, Mehnaz Kamal, Punya Sachdeva, Saurabh Kumar Jha, Shreesh Ojha, Dinesh Kumar, Niraj Kumar Jha, Hitesh Chopra, Shing Cheng Tan
    2024, 19 (1):  62-68.  doi: 10.4103/1673-5374.374139
    Abstract ( 239 )   PDF (1730KB) ( 199 )   Save
    Taurine is a sulfur-containing, semi-essential amino acid that occurs naturally in the body. It alternates between inflammation and oxidative stress-mediated injury in various disease models. As part of its limiting functions, taurine also modulates endoplasmic reticulum stress, Ca2+ homeostasis, and neuronal activity at the molecular level. Taurine effectively protects against a number of neurological disorders, including stroke, epilepsy, cerebral ischemia, memory dysfunction, and spinal cord injury. Although various therapies are available, effective management of these disorders remains a global challenge. Approximately 30 million people are affected worldwide. The design of taurine formation could lead to potential drugs/supplements for the health maintenance and treatment of central nervous system disorders. The general neuroprotective effects of taurine and the various possible underlying mechanisms are discussed in this review. This article is a good resource for understanding the general effects of taurine on various diseases. Given the strong evidence for the neuropharmacological efficacy of taurine in various experimental paradigms, it is concluded that this molecule should be considered and further investigated as a potential candidate for neurotherapeutics, with emphasis on mechanism and clinical studies to determine efficacy.
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    Lactate metabolism in neurodegenerative diseases
    Chaoguang Yang, Rui-Yuan Pan, Fangxia Guan, Zengqiang Yuan
    2024, 19 (1):  69-74.  doi: 10.4103/1673-5374.374142
    Abstract ( 241 )   PDF (652KB) ( 275 )   Save
    Lactate, a byproduct of glycolysis, was thought to be a metabolic waste until the discovery of the Warburg effect. Lactate not only functions as a metabolic substrate to provide energy but can also function as a signaling molecule to modulate cellular functions under pathophysiological conditions. The Astrocyte-Neuron Lactate Shuttle has clarified that lactate plays a pivotal role in the central nervous system. Moreover, protein lactylation highlights the novel role of lactate in regulating transcription, cellular functions, and disease development. This review summarizes the recent advances in lactate metabolism and its role in neurodegenerative diseases, thus providing optimal perspectives for future research.
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    Pathogenic and therapeutic role of exosomes in neurodegenerative disorders
    Christa C. Huber, Hongmin Wang
    2024, 19 (1):  75-79.  doi: 10.4103/1673-5374.375320
    Abstract ( 151 )   PDF (488KB) ( 117 )   Save
    Neurodegenerative disorders affect millions of people worldwide, and the prevalence of these disorders is only projected to rise as the number of people over 65 will drastically increase in the coming years. While therapies exist to aid in symptomatic relief, effective treatments that can stop or reverse the progress of each neurodegenerative disease are lacking. Recently, research on the role of extracellular vesicles as disease markers and therapeutics has been intensively studied. Exosomes, 30–150 nm in diameter, are one type of extracellular vesicles facilitating cell-to-cell communication. Exosomes are thought to play a role in disease propagation in a variety of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Accordingly, the exosomes derived from the patients are an invaluable source of disease biomarkers. On the other hand, exosomes, especially those derived from stem cells, could serve as a therapeutic for these disorders, as seen by a rapid increase in clinical trials investigating the therapeutic efficacy of exosomes in different neurological diseases. This review summarizes the pathological burden and therapeutic approach of exosomes in neurodegenerative disorders. We also highlight how heat shock increases the yield of exosomes while still maintaining their therapeutic efficacy. Finally, this review concludes with outstanding questions that remain to be addressed in exosomal research.
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    Impact of apolipoprotein E isoforms on sporadic Alzheimer’s disease: beyond the role of amyloid beta
    Madia Lozupone, Francesco Panza
    2024, 19 (1):  80-83.  doi: 10.4103/1673-5374.375316
    Abstract ( 119 )   PDF (1157KB) ( 94 )   Save
    The impact of apolipoprotein E (ApoE) isoforms on sporadic Alzheimer’s disease has long been studied; however, the influences of apolipoprotein E gene (APOE) on healthy and pathological human brains are not fully understood. ApoE exists as three common isoforms (ApoE2, ApoE3, and ApoE4), which differ in two amino acid residues. Traditionally, ApoE binds cholesterol and phospholipids and ApoE isoforms display different affinities for their receptors, lipids transport and distribution in the brain and periphery. The role of ApoE in the human depends on ApoE isoforms, brain regions, aging, and neural injury. APOE ε4 is the strongest genetic risk factor for sporadic Alzheimer’s disease, considering its role in influencing amyloid-beta metabolism. The exact mechanisms by which APOE gene variants may increase or decrease Alzheimer’s disease risk are not fully understood, but APOE was also known to affect directly and indirectly tau-mediated neurodegeneration, lipids metabolism, neurovascular unit, and microglial function. Consistent with the biological function of ApoE, ApoE4 isoform significantly altered signaling pathways associated with cholesterol homeostasis, transport, and myelination. Also, the rare protective APOE variants confirm that ApoE plays an important role in Alzheimer’s disease pathogenesis. The objectives of the present mini-review were to describe classical and new roles of various ApoE isoforms in Alzheimer’s disease pathophysiology beyond the deposition of amyloid-beta and to establish a functional link between APOE, brain function, and memory, from a molecular to a clinical level. APOE genotype also exerted a heterogeneous effect on clinical Alzheimer’s disease phenotype and its outcomes. Not only in learning and memory but also in neuropsychiatric symptoms that occur in a premorbid condition. Clarifying the relationships between Alzheimer’s disease-related pathology with neuropsychiatric symptoms, particularly suicidal ideation in Alzheimer’s disease patients, may be useful for elucidating also the underlying pathophysiological process and its prognosis. Also, the effects of anti-amyloid-beta drugs, recently approved for the treatment of Alzheimer’s disease, could be influenced by the APOE genotype.
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    Understanding the spectrum of non-motor symptoms in multiple sclerosis: insights from animal models
    Poornima D. E. Weerasinghe-Mudiyanselage, Joong-Sun Kim, Taekyun Shin, Changjong Moon
    2024, 19 (1):  84-91.  doi: 10.4103/1673-5374.375307
    Abstract ( 113 )   PDF (560KB) ( 114 )   Save
    Multiple sclerosis is a chronic autoimmune disease of the central nervous system and is generally considered to be a non-traumatic, physically debilitating neurological disorder. In addition to experiencing motor disability, patients with multiple sclerosis also experience a variety of non-motor symptoms, including cognitive deficits, anxiety, depression, sensory impairments, and pain. However, the pathogenesis and treatment of such non-motor symptoms in multiple sclerosis are still under research. Preclinical studies for multiple sclerosis benefit from the use of disease-appropriate animal models, including experimental autoimmune encephalomyelitis. Prior to understanding the pathophysiology and developing treatments for non-motor symptoms, it is critical to characterize the animal model in terms of its ability to replicate certain non-motor features of multiple sclerosis. As such, no single animal model can mimic the entire spectrum of symptoms. This review focuses on the non-motor symptoms that have been investigated in animal models of multiple sclerosis as well as possible underlying mechanisms. Further, we highlighted gaps in the literature to explain the non-motor aspects of multiple sclerosis in experimental animal models, which will serve as the basis for future studies.
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    The concept of gene therapy for glaucoma: the dream that has not come true yet
    Robert Sulak, Xiaonan Liu, Adrian Smedowski
    2024, 19 (1):  92-99.  doi: 10.4103/1673-5374.375319
    Abstract ( 132 )   PDF (1046KB) ( 240 )   Save
    Gene therapies, despite of being a relatively new therapeutic approach, have a potential to become an important alternative to current treatment strategies in glaucoma. Since glaucoma is not considered a single gene disease, the identified goals of gene therapy would be rather to provide neuroprotection of retinal ganglion cells, especially, in intraocular-pressure-independent manner. The most commonly reported type of vector for gene delivery in glaucoma studies is adeno-associated virus serotype 2 that has a high tropism to retinal ganglion cells, resulting in long-term expression and low immunogenic profile. The gene therapy studies recruit inducible and genetic animal models of optic neuropathy, like DBA/2J mice model of high-tension glaucoma and the optic nerve crush-model. Reported gene therapy-based neuroprotection of retinal ganglion cells is targeting specific genes translating to growth factors (i.e., brain derived neurotrophic factor, and its receptor TrkB), regulation of apoptosis and neurodegeneration (i.e., Bcl-xl, Xiap, FAS system, nicotinamide mononucleotide adenylyl transferase 2, Digit3 and Sarm1), immunomodulation (i.e., Crry, C3 complement), modulation of neuroinflammation (i.e., erythropoietin), reduction of excitotoxicity (i.e., CamKIIα) and transcription regulation (i.e., Max, Nrf2). On the other hand, some of gene therapy studies focus on lowering intraocular pressure, by impacting genes involved in both, decreasing aqueous humor production (i.e., aquaporin 1), and increasing outflow facility (i.e., COX2, prostaglandin F2α receptor, RhoA/RhoA kinase signaling pathway, MMP1, Myocilin). The goal of this review is to summarize the current state-of-art and the direction of development of gene therapy strategies for glaucomatous neuropathy.
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    Biomaterials-based anti-inflammatory treatment strategies for Alzheimer’s disease
    Jianjian Chu, Weicong Zhang, Yan Liu, Baofeng Gong, Wenbo Ji, Tong Yin, Chao Gao, Danqi Liangwen, Mengqi Hao, Cuimin Chen, Jianhua Zhuang, Jie Gao, You Yin
    2024, 19 (1):  100-115.  doi: 10.4103/1673-5374.374137
    Abstract ( 145 )   PDF (3886KB) ( 123 )   Save
    The current therapeutic drugs for Alzheimer’s disease only improve symptoms, they do not delay disease progression. Therefore, there is an urgent need for new effective drugs. The underlying pathogenic factors of Alzheimer’s disease are not clear, but neuroinflammation can link various hypotheses of Alzheimer’s disease; hence, targeting neuroinflammation may be a new hope for Alzheimer’s disease treatment. Inhibiting inflammation can restore neuronal function, promote neuroregeneration, reduce the pathological burden of Alzheimer’s disease, and improve or even reverse symptoms of Alzheimer’s disease. This review focuses on the relationship between inflammation and various pathological hypotheses of Alzheimer’s disease; reports the mechanisms and characteristics of small-molecule drugs (e.g., nonsteroidal anti-inflammatory drugs, neurosteroids, and plant extracts); macromolecule drugs (e.g., peptides, proteins, and gene therapeutics); and nanocarriers (e.g., lipid-based nanoparticles, polymeric nanoparticles, nanoemulsions, and inorganic nanoparticles) in the treatment of Alzheimer’s disease. The review also makes recommendations for the prospective development of anti-inflammatory strategies based on nanocarriers for the treatment of Alzheimer’s disease. 
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    Contribution of glial cells to the neuroprotective effects triggered by repetitive magnetic stimulation: a systematic review#br#
    Susana A. Ferreira, Nuno Pinto, Inês Serrenho, Maria Vaz Pato, Graça Baltazar
    2024, 19 (1):  116-123.  doi: 10.4103/1673-5374.374140
    Abstract ( 92 )   PDF (877KB) ( 85 )   Save
    Repetitive transcranial magnetic stimulation has been increasingly studied in different neurological diseases, and although most studies focus on its effects on neuronal cells, the contribution of non-neuronal cells to the improvement triggered by repetitive transcranial magnetic stimulation in these diseases has been increasingly suggested. To systematically review the effects of repetitive magnetic stimulation on non-neuronal cells two online databases, Web of Science and PubMed were searched for the effects of high-frequency-repetitive transcranial magnetic stimulation, low-frequency-repetitive transcranial magnetic stimulation, intermittent theta-burst stimulation, continuous theta-burst stimulation, or repetitive magnetic stimulation on non-neuronal cells in models of disease and in unlesioned animals or cells. A total of 52 studies were included. The protocol more frequently used was high-frequency-repetitive magnetic stimulation, and in models of disease, most studies report that high-frequency-repetitive magnetic stimulation led to a decrease in astrocyte and microglial reactivity, a decrease in the release of pro-inflammatory cytokines, and an increase of oligodendrocyte proliferation. The trend towards decreased microglial and astrocyte reactivity as well as increased oligodendrocyte proliferation occurred with intermittent theta-burst stimulation and continuous theta-burst stimulation. Few papers analyzed the low-frequency-repetitive transcranial magnetic stimulation protocol, and the parameters evaluated were restricted to the study of astrocyte reactivity and release of pro-inflammatory cytokines, reporting the absence of effects on these parameters. In what concerns the use of magnetic stimulation in unlesioned animals or cells, most articles on all four types of stimulation reported a lack of effects. It is also important to point out that the studies were developed mostly in male rodents, not evaluating possible differential effects of repetitive transcranial magnetic stimulation between sexes. This systematic review supports that through modulation of glial cells repetitive magnetic stimulation contributes to the neuroprotection or repair in various neurological disease models. However, it should be noted that there are still few articles focusing on the impact of repetitive magnetic stimulation on non-neuronal cells and most studies did not perform in-depth analyses of the effects, emphasizing the need for more studies in this field.
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    SIRT2 as a potential new therapeutic target for Alzheimer’s disease
    Noemi Sola-Sevilla, Elena Puerta
    2024, 19 (1):  124-131.  doi: 10.4103/1673-5374.375315
    Abstract ( 231 )   PDF (1193KB) ( 184 )   Save
    Alzheimer’s disease is the most common cause of dementia globally with an increasing incidence over the years, bringing a heavy burden to individuals and society due to the lack of an effective treatment. In this context, sirtuin 2, the sirtuin with the highest expression in the brain, has emerged as a potential therapeutic target for neurodegenerative diseases. This review summarizes and discusses the complex roles of sirtuin 2 in different molecular mechanisms involved in Alzheimer’s disease such as amyloid and tau pathology, microtubule stability, neuroinflammation, myelin formation, autophagy, and oxidative stress. The role of sirtuin 2 in all these processes highlights its potential implication in the etiology and development of Alzheimer’s disease. However, its presence in different cell types and its enormous variety of substrates leads to apparently contradictory conclusions when it comes to understanding its specific functions. Further studies in sirtuin 2 research with selective sirtuin 2 modulators targeting specific sirtuin 2 substrates are necessary to clarify its specific functions under different conditions and to validate it as a novel pharmacological target. This will contribute to the development of new treatment strategies, not only for Alzheimer’s disease but also for other neurodegenerative diseases.
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    Strategies for translating proteomics discoveries into drug discovery for dementia
    Aditi Halder, Eleanor Drummond
    2024, 19 (1):  132-139.  doi: 10.4103/1673-5374.373681
    Abstract ( 120 )   PDF (674KB) ( 134 )   Save
    Tauopathies, diseases characterized by neuropathological aggregates of tau including Alzheimer’s disease and subtypes of frontotemporal dementia, make up the vast majority of dementia cases. Although there have been recent developments in tauopathy biomarkers and disease-modifying treatments, ongoing progress is required to ensure these are effective, economical, and accessible for the globally ageing population. As such, continued identification of new potential drug targets and biomarkers is critical. “Big data” studies, such as proteomics, can generate information on thousands of possible new targets for dementia diagnostics and therapeutics, but currently remain underutilized due to the lack of a clear process by which targets are selected for future drug development. In this review, we discuss current tauopathy biomarkers and therapeutics, and highlight areas in need of improvement, particularly when addressing the needs of frail, comorbid and cognitively impaired populations. We highlight biomarkers which have been developed from proteomic data, and outline possible future directions in this field. We propose new criteria by which potential targets in proteomics studies can be objectively ranked as favorable for drug development, and demonstrate its application to our group’s recent tau interactome dataset as an example.
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    Clinical associations of corneal neuromas with ocular surface diseases
    Charmaine Jan Li Toh, Chang Liu, Isabelle Xin Yu Lee, Molly Tzu Yu Lin, Louis Tong, Yu-Chi Liu
    2024, 19 (1):  140-147.  doi: 10.4103/1673-5374.375308
    Abstract ( 119 )   PDF (1151KB) ( 104 )   Save
    Corneal neuromas, also termed microneuromas, refer to microscopic, irregularly-shaped enlargements of terminal subbasal nerve endings at sites of nerve damage or injury. The formation of corneal neuromas results from damage to corneal nerves, such as following corneal pathology or corneal or intraocular surgeries. Initially, denervated areas of sensory nerve fibers become invaded by sprouts of intact sensory nerve fibers, and later injured axons regenerate and new sprouts called neuromas develop. In recent years, analysis of corneal nerve abnormalities including corneal neuromas which can be identified using in vivo confocal microscopy, a non-invasive imaging technique with microscopic resolution, has been used to evaluate corneal neuropathy and ocular surface dysfunction. Corneal neuromas have been shown to be associated with clinical symptoms of discomfort and dryness of eyes, and are a promising surrogate biomarker for ocular surface diseases, such as neuropathic corneal pain, dry eye disease, diabetic corneal neuropathy, neurotrophic keratopathy, Sjögren’s syndrome, bullous keratopathy, post-refractive surgery, and others. In this review, we have summarized the current literature on the association between these ocular surface diseases and the presentation of corneal microneuromas, as well as elaborated on their pathogenesis, visualization via in vivo confocal microscopy, and utility in monitoring treatment efficacy. As current quantitative analysis on neuromas mainly relies on manual annotation and quantification, which is user-dependent and labor-intensive, future direction includes the development of artificial intelligence software to identify and quantify these potential imaging biomarkers in a more automated and sensitive manner, allowing it to be applied in clinical settings more efficiently. Combining imaging and molecular biomarkers may also help elucidate the associations between corneal neuromas and ocular surface diseases. 
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    Novel emphasis on somatostatinergic system in retinal ganglion cell neuroresilience
    Elisabetta Catalani, Davide Cervia
    2024, 19 (1):  148-149.  doi: 10.4103/1673-5374.374141
    Abstract ( 112 )   PDF (478KB) ( 44 )   Save
    The neuromodulatory peptide somatostatin (somatotropin release inhibiting factor, SRIF)-14 acts at multiple levels through five SRIF receptor subtypes (sst1 to sst5). SRIF-28 is also derived from a common propeptide translated from a single SRIF gene, although SRIF-14 is the predominant form in the mammalian nervous system. Due to its short half-life, synthetic SRIF analogs have been developed over the years and are available for therapeutic approaches. In particular, sandostatin (which contains octreotide) lanreotide and pasireotide are currently available in an injectable formulation. These analogs, alone or in combination with other agents (also as preoperative treatment), are used in clinical practice in endocrinological indications, i.e. acromegaly, Cushing’s disease, thyrotropinomas and gastroenteropancreatic neuroendocrine tumors, and in gastrointestinal indications, i.e. complications after pancreatic surgery and gastroesophageal varices in patients with cirrhosis (Gomes-Porras et al., 2020). The variable success rate of the administration of SRIF analogs depends on the particular aspects related to the pathology and the expression of sst1-sst5 at the cellular and tissue level, since the type and the amount of receptors are crucial factors for the drug response. Of interest, SRIF analogs represent an off-label treatment option in several conditions in the field of endocrinology, oncology, digestive, general surgery and ophthalmology, including diabetic retinopathy (DR)/diabetic macular edema and Graves’ orbitopathy. Indeed, SRIF analogs with potent neuroprotective properties are highly effective in protecting retinal cells from a variety of insults (Cammalleri et al., 2019). Since primary damage to retinal ganglion cells (RGCs) has been recognized as a major pathological feature in a number of vision-threatening diseases, this Perspective article will focus on recent preclinical evidence regarding the neuroprotective role of the SRIF system in RGCs. In particular, specific novel aspects related to the promising application of SRIF analogs in retinal neurodegeneration induced by metabolic insults will be discussed.
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    Consequences of early life stress on the structure and function of the adult mouse retina
    Juan S. Calanni, Ruth E. Rosenstein
    2024, 19 (1):  150-151.  doi: 10.4103/1673-5374.375325
    Abstract ( 71 )   PDF (774KB) ( 48 )   Save
    Early-life stress (ELS) refers to a period of environmental/social deprivation, physical, sexual or emotional abuse, neglect, severe and/or chronic trauma in the prenatal/early postnatal stage, which is closely related to many adverse psychiatric disorders later in life, such as depressive disorder, substance abuse, dysthymia, panic, anxiety, and suicidal behavior in adulthood (Waters and Gould, 2022). In addition to mood-related symptoms, a strong association between ELS and a wide range of adverse health outcomes in adulthood has been demonstrated, with increased risk of metabolic, musculoskeletal, neurological, respiratory, cardiovascular, and gastrointestinal symptoms (Wegman and Stetler, 2009). Therefore, ELS sequelae represent a serious public health concern. During childhood, social ties (mainly mother-infant relationship) play a key role in brain development and behavior in adulthood, and neonatal maternal separation (MS) has been shown to dramatically affect brain development, and increase the risk for several diseases (Cao et al., 2020). Since working with humans subjected to ELS is limited by the difficulty of finding a representative sample that experiences early adversities at the same stage, intensity, and duration, experimental approaches in animals are necessary to gain a deeper understanding of ELS-induced long-term consequences (Waters and Gould, 2022). In rodents, as in other mammals, the early postnatal environment is strongly determined by mother-pup interactions. In this regard, a mouse model of MS is widely recognized as a suitable model to mimic early adverse experiences, increasing depressive-like and/or anxiety-like behaviors in adulthood (Nishi, 2020), as demonstrated by behavioral tests, such as the sucrose preference test, the forced swim test, the open field test, the elevated plus-maze test, and the tail suspension tests (Nishi, 2020; Waters and Gould, 2022), some of which depend on the integrity of the visual system. In adult female Wistar rats, MS has been shown to induce a significant decrease in the thickness of the outer nuclear layer of the retina, as well as an increased retinal microglial reactivity and glial fibrillary acidic protein (a gliotic marker)-immunoreactivity (Grigoruta et al., 2020). However, despite that numerous effects of ELS on the central nervous system have been reported, its effects on the retina and visual system of adult mice remain unknown. 
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    Tau’s function and dysfunction in the brain: when small changes have big consequences
    Miguel Portillo, Debra Toiber
    2024, 19 (1):  152-153.  doi: 10.4103/1673-5374.373682
    Abstract ( 89 )   PDF (463KB) ( 69 )   Save
    With the increase of life expectancy and population growth, neurodegenerative diseases have risen too and are projected to be a major health public concern by 2050. Neurodegenerative diseases are characterized by the progressive decline of cognitive function leading to the subsequent loss of autonomy. Although the underlying causes of neurodegeneration are not well understood, aging is the main risk factor. Interestingly, more than 17 neurodegenerative diseases present Tau protein dysregulation as a hallmark of degeneration. Tau protein, which can be hyperphosphorylated, hyperacetylated, cleaved, alternative spliced, mutated, and form neurofibrillary tangles (NFT’s), has multiple cellular functions that could potentially be compromised and lead to neurodegeneration. Nevertheless, Tau’s biology remains largely unknown to this day despite its wide interest in the scientific community. In this perspective, we highlight some of the layers of regulation that make Tau’s universe so elusive and challenging for its apprehension and the ramifications of such complexity with emphasis at the nucleus.     
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    Advanced brain organoids for neuroinflammation disease modeling
    Sonia Sabate-Soler, Henry Kurniawan, Jens Christian Schwamborn
    2024, 19 (1):  154-155.  doi: 10.4103/1673-5374.375321
    Abstract ( 162 )   PDF (600KB) ( 81 )   Save
    Brain organoids mimic closely the embryonic human brain: Over the last decade, the development of human organoid systems has evolved rapidly. Different tissues have been modeled with organoids, such as the gut, lung, liver, kidney retina and brain. These systems have a high cellular heterogeneity, with many cell types integrated into the same system. Organoids’ cellular populations interact between and amongst each other in a cellular and molecular level, which represents an advantage with respects to monolayer 2D cell culture systems.
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    Beyond dentistry: could prevention and screening for neurodegenerative diseases start in the dental office?
    Francesca R. Buccellato, Daniela Galimberti, Gianluca M. Tartaglia
    2024, 19 (1):  156-157.  doi: 10.4103/1673-5374.375323
    Abstract ( 78 )   PDF (354KB) ( 54 )   Save
    The differential diagnosis of neurodegenerative diseases is complex and relies on clinical assessment, biomarker levels in cerebrospinal fluid, neuroimaging and neuropsychological assessment. The efforts of the scientific community are focused on two aspects: a) the discovery of minimally invasive biomarkers; b) the discovery of early biomarkers that can predict the progression to clinical disease in the pre-symptomatic stage of a disease. Considering the impact of the number of patients affected by chronic neurodegenerative diseases on public health expenditures, early diagnosis seems to be a primary need of our society.
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    A cup of coffee for a brain long life
    Chiara Porro, Antonia Cianciulli, Maria Antonietta Panaro
    2024, 19 (1):  158-159.  doi: 10.4103/1673-5374.375324
    Abstract ( 105 )   PDF (556KB) ( 75 )   Save
    Coffee is one of the world’s favorite and most popular beverages, the third most popular beverage after water and tea. For many people, it is an indispensable habit before going to work and a socialization tool for the rest of the day. In general, the average consumption varies from 2 to 6 cups per day. What are the health implications? Given this consumption, the benefits are actually greater than the risks. This is the conclusion of a careful study published in the New England Journal of Medicine (van Dam et al., 2020).
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    Bioactive material promotes long-distance regeneration of optic nerve to restore visual functions
    Kai Liu
    2024, 19 (1):  160-160.  doi: 10.4103/1673-5374.375326
    Abstract ( 237 )   PDF (202KB) ( 146 )   Save
    Visual system is vital to human beings. Unfortunately, the optic nerve lacks the ability to regenerate after injury. Therefore, long-distance regeneration of the optic nerve is a major unsolved medical problem in the world (Laha et al., 2017). Recently, Li and So groups’ study showed that the bioactive material (ciliary neurotrophic factor [CNTF]-chitosan) could promote long-distance regeneration of the completely transected optic nerve in adult rats and partially restored the visual functions (Liu et al., 2023). This study sheds light on the clinical potential for repairing the severely injured optic nerve.
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    Spi1 regulates the microglial/macrophage inflammatory response via the PI3K/AKT/mTOR signaling pathway after intracerebral hemorrhage
    Guoqiang Zhang, Jianan Lu, Jingwei Zheng, Shuhao Mei, Huaming Li, Xiaotao Zhang, An Ping, Shiqi Gao, Yuanjian Fang, Jun Yu
    2024, 19 (1):  161-170.  doi: 10.4103/1673-5374.375343
    Abstract ( 276 )   PDF (7740KB) ( 113 )   Save

    Preclinical and clinical studies have shown that microglia and macrophages participate in a multiphasic brain damage repair process following intracerebral hemorrhage. The E26 transformation-specific sequence-related transcription factor Spi1 regulates microglial/macrophage commitment and maturation. However, the effect of Spi1 on intracerebral hemorrhage remains unclear. In this study, we found that Spi1 may regulate recovery from the neuroinflammation and neurofunctional damage caused by intracerebral hemorrhage by modulating the microglial/macrophage transcriptome. We showed that high Spi1 expression in microglia/macrophages after intracerebral hemorrhage is associated with the activation of many pathways that promote phagocytosis, glycolysis, and autophagy, as well as debris clearance and sustained remyelination. Notably, microglia with higher levels of Spi1 expression were characterized by activation of pathways associated with a variety of hemorrhage-related cellular processes, such as complement activation, angiogenesis, and coagulation. In conclusion, our results suggest that Spi1 plays a vital role in the microglial/macrophage inflammatory response following intracerebral hemorrhage. This new insight into the regulation of Spi1 and its target genes may advance our understanding of neuroinflammation in intracerebral hemorrhage and provide therapeutic targets for patients with intracerebral hemorrhage. 

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    Transcriptomic and bioinformatics analysis of the mechanism by which erythropoietin promotes recovery from traumatic brain injury in mice
    Weilin Tan, Jun Ma, Jiayuanyuan Fu, Biying Wu, Ziyu Zhu, Xuekang Huang, Mengran Du, Chenrui Wu, Ehab Balawi, Qiang Zhou, Jie Zhang, Zhengbu Liao
    2024, 19 (1):  171-179.  doi: 10.4103/1673-5374.374135
    Abstract ( 102 )   PDF (4349KB) ( 124 )   Save
    Recent studies have found that erythropoietin promotes the recovery of neurological function after traumatic brain injury. However, the precise mechanism of action remains unclear. In this study, we induced moderate traumatic brain injury in mice by intraperitoneal injection of erythropoietin for 3 consecutive days. RNA sequencing detected a total of 4065 differentially expressed RNAs, including 1059 mRNAs, 92 microRNAs, 799 long non-coding RNAs, and 2115 circular RNAs. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses revealed that the coding and non-coding RNAs that were differentially expressed after traumatic brain injury and treatment with erythropoietin play roles in the axon guidance pathway, Wnt pathway, and MAPK pathway. Constructing competing endogenous RNA networks showed that regulatory relationship between the differentially expressed non-coding RNAs and mRNAs. Because the axon guidance pathway was repeatedly enriched, the expression of Wnt5a and Ephb6, key factors in the axonal guidance pathway, was assessed. Ephb6 expression decreased and Wnt5a expression increased after traumatic brain injury, and these effects were reversed by treatment with erythropoietin. These findings suggest that erythropoietin can promote recovery of nerve function after traumatic brain injury through the axon guidance pathway. 
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    Photobiomodulation inhibits the expression of chondroitin sulfate proteoglycans after spinal cord injury via the Sox9 pathway
    Zhihao Zhang, Zhiwen Song, Liang Luo, Zhijie Zhu, Xiaoshuang Zuo, Cheng Ju, Xuankang Wang, Yangguang Ma, Tingyu Wu, Zhou Yao, Jie Zhou, Beiyu Chen, Tan Ding, Zhe Wang, Xueyu Hu
    2024, 19 (1):  180-189.  doi: 10.4103/1673-5374.374136
    Abstract ( 153 )   PDF (3846KB) ( 134 )   Save
    Both glial cells and glia scar greatly affect the development of spinal cord injury and have become hot spots in research on spinal cord injury treatment. The cellular deposition of dense extracellular matrix proteins such as chondroitin sulfate proteoglycans inside and around the glial scar is known to affect axonal growth and be a major obstacle to autogenous repair. These proteins are thus candidate targets for spinal cord injury therapy. Our previous studies demonstrated that 810 nm photobiomodulation inhibited the formation of chondroitin sulfate proteoglycans after spinal cord injury and greatly improved motor function in model animals. However, the specific mechanism and potential targets involved remain to be clarified. In this study, to investigate the therapeutic effect of photobiomodulation, we established a mouse model of spinal cord injury by T9 clamping and irradiated the injury site at a power density of 50 mW/cm2 for 50 minutes once a day for 7 consecutive days. We found that photobiomodulation greatly restored motor function in mice and downregulated chondroitin sulfate proteoglycan expression in the injured spinal cord. Bioinformatics analysis revealed that photobiomodulation inhibited the expression of proteoglycan-related genes induced by spinal cord injury, and versican, a type of proteoglycan, was one of the most markedly changed molecules. Immunofluorescence staining showed that after spinal cord injury, versican was present in astrocytes in spinal cord tissue. The expression of versican in primary astrocytes cultured in vitro increased after inflammation induction, whereas photobiomodulation inhibited the expression of versican. Furthermore, we found that the increased levels of p-Smad3, p-P38 and p-Erk in inflammatory astrocytes were reduced after photobiomodulation treatment and after delivery of inhibitors including FR 180204, (E)-SIS3, and SB 202190. This suggests that Smad3/Sox9 and MAPK/Sox9 pathways may be involved in the effects of photobiomodulation. In summary, our findings show that photobiomodulation modulates the expression of chondroitin sulfate proteoglycans, and versican is one of the key target molecules of photobiomodulation. MAPK/Sox9 and Smad3/Sox9 pathways may play a role in the effects of photobiomodulation on chondroitin sulfate proteoglycan accumulation after spinal cord injury.
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    Chemokine platelet factor 4 accelerates peripheral nerve regeneration by regulating Schwann cell activation and axon elongation
    Miao Gu, Xiao Cheng, Di Zhang, Weiyan Wu, Yi Cao, Jianghong He
    2024, 19 (1):  190-195.  doi: 10.4103/1673-5374.375346
    Abstract ( 155 )   PDF (2315KB) ( 150 )   Save
    Schwann cells in peripheral nerves react to traumatic nerve injury by attempting to grow and regenerate. However, it is unclear what factors play a role in this process. In this study, we searched a GEO database and found that expression of platelet factor 4 was markedly up-regulated after sciatic nerve injury. Platelet factor is an important molecule in cell apoptosis, differentiation, survival, and proliferation. Further, polymerase chain reaction and immunohistochemical staining confirmed the change in platelet factor 4 in the sciatic nerve at different time points after injury. Enzyme-linked immunosorbent assay confirmed that platelet factor 4 was secreted by Schwann cells. We also found that silencing platelet factor 4 decreased the proliferation and migration of primary cultured Schwann cells, while exogenously applied platelet factor 4 stimulated Schwann cell proliferation and migration and neuronal axon growth. Furthermore, knocking out platelet factor 4 inhibited the proliferation of Schwann cells in injured rat sciatic nerve. These findings suggest that Schwann cell-secreted platelet factor 4 may facilitate peripheral nerve repair and regeneration by regulating Schwann cell activation and axon growth. Thus, platelet factor 4 may be a potential therapeutic target for traumatic peripheral nerve injury.
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    CHCHD2 Thr61Ile mutation impairs F1F0-ATPase assembly in in vitro and in vivo models of Parkinson’s disease
    Xiang Chen, Yuwan Lin, Zhiling Zhang, Yuting Tang, Panghai Ye, Wei Dai, Wenlong Zhang, Hanqun Liu, Guoyou Peng, Shuxuan Huang, Jiewen Qiu, Wenyuan Guo, Xiaoqin Zhu, Zhuohua Wu, Yaoyun Kuang, Pingyi Xu, Miaomiao Zhou
    2024, 19 (1):  196-204.  doi: 10.4103/1673-5374.378010
    Abstract ( 100 )   PDF (2125KB) ( 229 )   Save
    Mitochondrial dysfunction is a significant pathological alteration that occurs in Parkinson’s disease (PD), and the Thr61Ile (T61I) mutation in coiled-coil helix coiled-coil helix domain containing 2 (CHCHD2), a crucial mitochondrial protein, has been reported to cause Parkinson’s disease. F1F0-ATPase participates in the synthesis of cellular adenosine triphosphate (ATP) and plays a central role in mitochondrial energy metabolism. However, the specific roles of wild-type (WT) CHCHD2 and T61I-mutant CHCHD2 in regulating F1F0-ATPase activity in Parkinson’s disease, as well as whether CHCHD2 or CHCHD2 T61I affects mitochondrial function through regulating F1F0-ATPase activity, remain unclear. Therefore, in this study, we expressed WT CHCHD2 and T61I-mutant CHCHD2 in an MPP+-induced SH-SY5Y cell model of PD. We found that CHCHD2 protected mitochondria from developing MPP+-induced dysfunction. Under normal conditions, overexpression of WT CHCHD2 promoted F1F0-ATPase assembly, while T61I-mutant CHCHD2 appeared to have lost the ability to regulate F1F0-ATPase assembly. In addition, mass spectrometry and immunoprecipitation showed that there was an interaction between CHCHD2 and F1F0-ATPase. Three weeks after transfection with AAV-CHCHD2 T61I, we intraperitoneally injected 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into mice to establish an animal model of chronic Parkinson’s disease and found that exogenous expression of the mutant protein worsened the behavioral deficits and dopaminergic neurodegeneration seen in this model. These findings suggest that WT CHCHD2 can alleviate mitochondrial dysfunction in PD by maintaining F1F0-ATPase structure and function.
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    The MORC2 p.S87L mutation reduces proliferation of pluripotent stem cells derived from a patient with the spinal muscular atrophy-like phenotype by inhibiting proliferation-related signaling pathways
    Sen Zeng, Honglan Yang, Binghao Wang, Yongzhi Xie, Ke Xu, Lei Liu, Wanqian Cao, Xionghao Liu, Beisha Tang, Mujun Liu, Ruxu Zhang
    2024, 19 (1):  205-211.  doi: 10.4103/1673-5374.375347
    Abstract ( 113 )   PDF (2824KB) ( 119 )   Save

    Mutations in the microrchidia CW-type zinc finger protein 2 (MORC2) gene are the causative agent of Charcot-Marie-Tooth disease type 2Z (CMT2Z), and the hotspot mutation p.S87L is associated with a more severe spinal muscular atrophy-like clinical phenotype. The aims of this study were to determine the mechanism of the severe phenotype caused by the MORC2 p.S87L mutation and to explore potential treatment strategies. Epithelial cells were isolated from urine samples from a spinal muscular atrophy (SMA)-like patient (MORC2 p.S87L), a CMT2Z patient (MORC2 p.Q400R), and a healthy control and induced to generate pluripotent stem cells, which were then differentiated into motor neuron precursor cells. Next-generation RNA sequencing followed by KEGG pathway enrichment analysis revealed that differentially expressed genes involved in the PI3K/Akt and MAPK/ERK signaling pathways were enriched in the p.S87L SMA-like patient group and were significantly downregulated in induced pluripotent stem cells. Reduced proliferation was observed in the induced pluripotent stem cells and motor neuron precursor cells derived from the p.S87L SMA-like patient group compared with the CMT2Z patient group and the healthy control. G0/G1 phase cell cycle arrest was observed in induced pluripotent stem cells derived from the p.S87L SMA-like patient. MORC2 p.S87L-specific antisense oligonucleotides (p.S87L-ASO-targeting) showed significant efficacy in improving cell proliferation and activating the PI3K/Akt and MAPK/ERK pathways in induced pluripotent stem cells. However, p.S87L-ASO-targeting did not rescue proliferation of motor neuron precursor cells. These findings suggest that downregulation of the PI3K/Akt and MAPK/ERK signaling pathways leading to reduced cell proliferation and G0/G1 phase cell cycle arrest in induced pluripotent stem cells might be the underlying mechanism of the severe p.S87L SMA-like phenotype. p.S87L-ASO-targeting treatment can alleviate disordered cell proliferation in the early stage of pluripotent stem cell induction. 

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    Increasing β-hexosaminidase A activity using genetically modified mesenchymal stem cells
    Alisa A. Shaimardanova, Daria S. Chulpanova, Valeriya V. Solovуeva, Shaza S. Issa, Aysilu I. Mullagulova, Angelina A. Titova, Yana O. Mukhamedshina, Anna V. Timofeeva, Alexander M. Aimaletdinov, Islam R. Nigmetzyanov, Albert A. Rizvanov
    2024, 19 (1):  212-219.  doi: 10.4103/1673-5374.375328
    Abstract ( 106 )   PDF (1933KB) ( 174 )   Save
    GM2 gangliosidoses are a group of autosomal-recessive lysosomal storage disorders. These diseases result from a deficiency of lysosomal enzyme β-hexosaminidase A (HexA), which is responsible for GM2 ganglioside degradation. HexA deficiency causes the accumulation of GM2-gangliosides mainly in the nervous system cells, leading to severe progressive neurodegeneration and neuroinflammation. To date, there is no treatment for these diseases. Cell-mediated gene therapy is considered a promising treatment for GM2 gangliosidoses. This study aimed to evaluate the ability of genetically modified mesenchymal stem cells (MSCs-HEXA-HEXB) to restore HexA deficiency in Tay-Sachs disease patient cells, as well as to analyze the functionality and biodistribution of MSCs in vivo. The effectiveness of HexA deficiency cross-correction was shown in mutant MSCs upon interaction with MSCs-HEXA-HEXB. The results also showed that the MSCs-HEXA-HEXB express the functionally active HexA enzyme, detectable in vivo, and intravenous injection of the cells does not cause an immune response in animals. These data suggest that genetically modified mesenchymal stem cells have the potentials to treat GM2 gangliosidoses. 
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    Morphological disruption and visual tuning alterations in the primary visual cortex in glaucoma (DBA/2J) mice
    Yin Yang, Zhaoxi Yang, Maoxia Lv, Ang Jia, Junjun Li, Baitao Liao, Jing’an Chen, Zhengzheng Wu, Yi Shi, Yang Xia, Dezhong Yao, Ke Chen
    2024, 19 (1):  220-225.  doi: 10.4103/1673-5374.375341
    Abstract ( 217 )   PDF (1470KB) ( 119 )   Save
    Glaucoma is a leading cause of irreversible blindness worldwide, and previous studies have shown that, in addition to affecting the eyes, it also causes abnormalities in the brain. However, it is not yet clear how the primary visual cortex (V1) is altered in glaucoma. This study used DBA/2J mice as a model for spontaneous secondary glaucoma. The aim of the study was to compare the electrophysiological and histomorphological characteristics of neurons in the V1 between 9-month-old DBA/2J mice and age-matched C57BL/6J mice. We conducted single-unit recordings in the V1 of light-anesthetized mice to measure the visually induced responses, including single-unit spiking and gamma band oscillations. The morphology of layer II/III neurons was determined by neuronal nuclear antigen staining and Nissl staining of brain tissue sections. Eighty-seven neurons from eight DBA/2J mice and eighty-one neurons from eight C57BL/6J mice were examined. Compared with the C57BL/6J group, V1 neurons in the DBA/2J group exhibited weaker visual tuning and impaired spatial summation. Moreover, fewer neurons were observed in the V1 of DBA/2J mice compared with C57BL/6J mice. These findings suggest that DBA/2J mice have fewer neurons in the V1 compared with C57BL/6J mice, and that these neurons have impaired visual tuning. Our findings provide a better understanding of the pathological changes that occur in V1 neuron function and morphology in the DBA/2J mouse model. This study might offer some innovative perspectives regarding the treatment of glaucoma. 
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    Progress in neurorehabilitation research and the support by the National Natural Science Foundation of China from 2010 to 2022
    Qian Tao, Honglu Chao, Dong Fang, Dou Dou
    2024, 19 (1):  226-232.  doi: 10.4103/1673-5374.375342
    Abstract ( 354 )   PDF (1474KB) ( 667 )   Save
    The National Natural Science Foundation of China is one of the major funding agencies for neurorehabilitation research in China. This study reviews the frontier directions and achievements in the field of neurorehabilitation in China and worldwide. We used data from the Web of Science Core Collection (WoSCC) database to analyze the publications and data provided by the National Natural Science Foundation of China to analyze funding information. In addition, the prospects for neurorehabilitation research in China are discussed. From 2010 to 2022, a total of 74,220 publications in neurorehabilitation were identified, with there being an overall upward tendency. During this period, the National Natural Science Foundation of China has funded 476 research projects with a total funding of 192.38 million RMB to support neurorehabilitation research in China. With the support of the National Natural Science Foundation of China, China has made some achievements in neurorehabilitation research. Research related to neurorehabilitation is believed to be making steady and significant progress in China.
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