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15 November 2024, Volume 19 Issue 11 Previous Issue   

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A sphingolipid message promotes neuronal health across generations Wenyue Wang, Roger Pocock 2024, 19 (11):  2325-2326.  doi: 10.4103/1673-5374.391333 Abstract ( 125 )   PDF (575KB) ( 21 )   Save Maternal nutrition can affect brain function of offspring in later life (Fitzgerald et al., 2020). Emerging studies have also shown that the maternal environment can modify susceptibility to neurodegenerative disease (Boots et al., 2023). Transmission of environmental information from mother to offspring depends on maternal nutrient provisioning. In the nematode Caenorhabditis elegans, maternal yolk, which is synthesized in the intestine and transferred to nourish oocytes and early embryos, can provide extranuclear inheritance factors to mediate phenotypic plasticity across generations. However, the molecular mechanisms of regulating such intergenerational effects remain largely unknown. Related Articles | Metrics

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Krüppel-like factor 2 (KLF2), a potential target for neuroregeneration Surajit Hansda, Prateeksha Prateeksha, Hiranmoy Das 2024, 19 (11):  2327-2328.  doi: 10.4103/NRR.NRR-D-23-01758 Abstract ( 95 )   PDF (719KB) ( 34 )   Save Neurological disorders and injuries lead to the impairment or depletion of neurons in terms of quantity, structure, or function, resulting in the loss of cognitive, emotional, and physical abilities in human beings. This, in turn, accompanies the shortfall of valuable human resources and economic potential, causing a detriment to society. Addressing these challenges, therefore, becomes imperative not only from a humanitarian perspective but also as a means of preserving human capital and bolstering economic prosperity. Extensive scientific efforts have been directed toward developing effective, precise, and safe therapeutics for neuroregeneration, encompassing neurogenesis, neurorepair, and neuroprotection to enhance neurological recovery and health. Comprehending the molecular complexity of neuron damage and recovery is imperative to unravel the mysteries of the brain’s resilience. This understanding opens a new avenue for developing innovative treatments by targeting the specific pathways and molecules involved in several neurological illnesses. These neurological diseases include stroke, epilepsy, Alzheimer’s disease, learning impairments, neuromuscular disorders, autism, attention deficit disorder, brain tumors, cerebral palsy, and acute neural injuries.  Related Articles | Metrics

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Defined hydrogels for spinal cord organoids: challenges and potential applications Wai Hon Chooi, Yuewen Wu, Shi-Yan Ng 2024, 19 (11):  2329-2330.  doi: 10.4103/NRR.NRR-D-23-01665 Abstract ( 118 )   PDF (1004KB) ( 56 )   Save Organoids of the central nervous system, primarily derived from pluripotent stem cells or neural stem cells, are three-dimensional tissue cultures with self-organizing properties. When exposed to the right combinations of signals, they differentiate into a 3D tissue consisting of complex cytoarchitecture and native cell types, including various neuron subtypes and glial cells. These features closely mimic native tissues, making them invaluable for developmental studies and disease modeling. In recent years, spinal cord organoids (SCOs) have been developed to investigate spinal cord development, injuries, and various neurological disorders. As an integral part of the central nervous system, SCOs play a vital role and serve as a site for studying both neurodevelopment and neurodegenerative diseases. Related Articles | Metrics

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Neuronal trafficking as a key to functional recovery in immune-mediated neuropathies Felix Kohle, Michael Schroeter 2024, 19 (11):  2331-2332.  doi: 10.4103/NRR.NRR-D-23-01676 Abstract ( 65 )   PDF (914KB) ( 29 )   Save Immune-mediated neuropathies are rare diseases of the peripheral nervous system (PNS), substantially affecting patients’ functionality and quality of life. They are amenable to immunomodulatory treatments, which in many cases stabilize disease progression, but long-term deficits persist in many patients. Such long-term deficits are particularly observed in monophasic autoimmune neuropathies like Guillain-Barré syndrome and also in chronic variants, e.g., chronic inflammatory demyelinating neuropathy (Fadia et al., 2019). In chronic immune neuropathies, we increasingly recognize a slowly progressing degeneration of neurons despite highly active immune therapies – a fact that has been re-discovered in multiple sclerosis, the prototypic central nervous system (CNS) immune disease. Related Articles | Metrics

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Advancements in personalized stem cell models for aging-related neurodegenerative disorders Mingxi Weng, Ralf Jauch 2024, 19 (11):  2333-2334.  doi: 10.4103/NRR.NRR-D-23-01793 Abstract ( 140 )   PDF (516KB) ( 50 )   Save Neurodegenerative diseases (NDDs) are a class of disorders characterized by the gradual loss or malfunction of specific cell populations in the nervous system, which can be triggered by genetic or environmental factors. As a result, patients often experience a decline in mobility, sensation, memory, and cognition, which can ultimately lead to a fatal outcome. The global incidence of NDDs, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis, is increasing. Many NDDs are associated with aging, and they pose significant challenges to affected families, healthcare systems, and societies, which will only be exacerbated by the current demographic megatrend. Clinical management of NDDs is primarily focused on mitigating physical or mental impairment, slowing disease progression, and providing palliative care. Despite extensive research efforts spanning decades, there are currently no effective cures for NDDs. This is largely due to a limited understanding of disease mechanisms, the heterogeneity of the pathophysiology, and the failure to identify specific pathways and molecular targets that cause the diseases. For example, most ALS cases are sporadic without clear-cut genetic cause and a unique patient-specific etiology. Disease-associated cell types, such as neurons in the patient’s brain, are not easily accessible for clinical evaluations. The lack of patient biopsies and the scarcity of representative animal models hinder mechanistic studies and the discovery of potential treatments. Related Articles | Metrics

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New insights into astrocyte diversity from the lens of transcriptional regulation and their implications for neurodegenerative disease treatments Ibrahim Olabayode Saliu, Guoyan Zhao 2024, 19 (11):  2335-2336.  doi: 10.4103/NRR.NRR-D-23-01790 Abstract ( 80 )   PDF (3132KB) ( 45 )   Save Astrocytes are a major glial cell type in the central nervous system, and they provide trophic and metabolic support to neurons. In addition to these roles, they play crucial roles in modulating synaptic functions, development, and pruning (Brandebura et al., 2023). Astrocytes become reactive (activated) by undergoing morphological, molecular, and functional alterations in response to neuropathology such as in injuries and neurodegenerative diseases (NDs) (Escartin et al., 2021). The pathological significance of reactive astrocytes has been implicated in the onset and progression of NDs, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Lewy body disease, and Huntington’s disease. Heterogeneous responses of astrocytes have been seen to exert detrimental and/or beneficial effects on the brain depending on the stimuli. For example, astrocytes have been reported to initiate inflammation and inhibit axon regeneration or withstand neuronal insults and improve recovery (Brandebura et al., 2023). Reactive astrocytes can mitigate disease outcomes by releasing molecules that promote cell repair or exacerbate disease outcomes by releasing molecules that promote the formation of glial scars to prevent axonal regeneration or cause cell death (Brandebura et al., 2023). Therefore, it is critical to understand the molecular mechanisms that regulate the inherent cellular contribution of astrocytes to neuronal degeneration and how they can be manipulated to prevent degeneration or even facilitate neuronal regeneration in NDs. In this perspective, we discuss recent findings on the complexities in the heterogeneous response of astrocytes in NDs. We also emphasize that understanding astrocyte subtypes and their transcriptional profiles in different brain regions and different disease conditions is crucial for the development of effective therapies. Related Articles | Metrics

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Harnessing endothelial cells and vascularization strategies for nerve regeneration Papon Muangsanit, Poppy Smith 2024, 19 (11):  2337-2338.  doi: 10.4103/NRR.NRR-D-23-01840 Abstract ( 86 )   PDF (631KB) ( 46 )   Save Peripheral nerves are essential components of the human body’s communication system, transmitting signals between the central nervous system and various body parts. Damage resulting from trauma or disease can result in debilitating sensory and motor deficits. Nerve injuries, particularly those resulting in significant gaps in the nerve tissue, pose a formidable challenge for clinicians and researchers. Despite their limitations, including limited availability and donor site morbidity, nerve autografts remain the clinical gold standard for treating nerve injuries. Tissue engineering seeks to provide an alternative to the autograft with the fabrication of nerve repair constructs. These constructs have the potential to overcome the limitations of the autograft while still harnessing autograft biology with aligned biomaterials and therapeutic cells. A crucial aspect of nerve tissue engineering is the establishment of vascularization within the regenerating nerve tissue. This process plays a pivotal role in providing oxygen and nutrients to implanted cells, ensuring their long-term survival. Over recent years, it has become ever more apparent that the role of blood vessels in nerve regeneration extends beyond vascularization. Blood vessels, and the endothelial cells that form the vessel inner lining, serve prominent structural, regulatory, and modulatory roles in nerve regeneration (Shen et al., 2004; Cattin et al., 2015; Grasman and Kaplan, 2017; Witjas et al., 2019; Fornasari et al., 2022; Huang et al., 2023). The exploitation of this knowledge has led to the development of various effective nerve injury treatments in animal models (Muangsanit et al., 2021; Thibodeau et al., 2022; Huang et al., 2023). Therefore, the intricate interplay between vascularization and nerve tissue engineering could be the key to improving engineered nerve repair constructs. Related Articles | Metrics

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Unraveling the potential of acute intermittent hypoxia as a strategy for inducing robust repair in multiple sclerosis Valerie M.K. Verge, Nataliya Tokarska, Justin M. Naniong 2024, 19 (11):  2339-2340.  doi: 10.4103/NRR.NRR-D-23-01663 Abstract ( 58 )   PDF (529KB) ( 30 )   Save Multiple sclerosis (MS) is a debilitating inflammatory disease of the central nervous system characterized by immune-mediated segmental demyelination and variable degrees of axonal and neuronal degeneration that contribute to disability. Inducing efficient and effective repair programs following demyelination is a major goal and challenge in MS. Conventional MS therapies focus largely on modulating the immune aspects of the disease contributing to lesions. While this alleviates some symptoms and mitigates damage, it does not tackle the fundamental challenge of effective remyelination, which few MS patients experience, especially in the progressive phase of the disease. Related Articles | Metrics

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Next-generation regenerative therapy for ischemic stroke using peripheral blood mononuclear cells Masato Kanazawa, Itaru Ninomiya, Yutaka Otsu, Masahiro Hatakeyama 2024, 19 (11):  2341-2342.  doi: 10.4103/NRR.NRR-D-23-01784 Abstract ( 131 )   PDF (712KB) ( 48 )   Save Stroke is the second leading cause of death and the third leading cause of disability worldwide after heart disease. Researchers predict that stroke deaths and permanent disabilities will increase worldwide by the year 2050. Single-target therapies may be insufficient, because ischemic cerebral injury involves several mechanisms. Cell-mediated therapies are ideal, because they target multiple cell types to enhance protection and recovery. Sources for cell therapy include bone marrow-derived mesenchymal and embryonic stem cells. Although clinical trials on the administration of autologous mesenchymal stem cells have shown improved functional outcomes after ischemic stroke, the number of these cells is limited. Therefore, it requires time to obtain sufficient functionally mature cells for treatment. Simple and abundant cell sources, such as peripheral blood cells, are suitable for clinical applications.  Related Articles | Metrics

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Potential of molecular chaperones for treating Alzheimer’s disease Gefei Chen, Jan Johansson 2024, 19 (11):  2343-2344.  doi: 10.4103/NRR.NRR-D-23-01927 Abstract ( 113 )   PDF (606KB) ( 36 )   Save Alzheimer’s disease (AD) is the most prevalent form of dementia, i.e., progressive memory loss and profound cognitive dysfunction, resulting in a considerable societal burden. At the neuropathological level, the brains of AD patients exhibit amyloid-β (Aβ) plaques, neurofibrillary tangles, and neuroinflammation (Sala Frigerio and De Strooper, 2016). The growing number of individuals affected with AD underscores the pressing need for the development of effective treatments, and a cure remains elusive. The pathogenesis of AD involves intricate molecular and cellular mechanisms that lead to progressive neurodegeneration and cognitive decline. A central tenet of AD pathogenesis is the amyloid cascade hypothesis, which posits that the accumulation of Aβ peptides plays a pivotal role in disease progression. Aβ derives from the amyloid precursor protein (APP) by BACE1 (β-secretase) and γ-secretase cleavages, and aggregates into plaques that eventually disrupt neuronal function. Concurrently, abnormal phosphorylation of the tau protein leads to the formation of neurofibrillary tangles, contributing to neuronal degeneration. Neuroinflammation, oxidative stress, mitochondrial dysfunction, and synaptic impairment further compound the pathology (Sala Frigerio and De Strooper, 2016). The intricate interplay of these phenomena underscores the challenges in treating AD, necessitating innovative therapeutic approaches to halt or slow disease progression effectively. Recently, monoclonal antibody drugs, like Aducanumab, Lecanemab, and Donanemab, have shown the ability to decelerate memory and cognitive decline in phase III clinical trials of early-stage AD (Boxer and Sperling, 2023). Aducanumab is designed to bind Aβ aggregates in both the oligomeric and fibrillar states rather than amyloid monomers, while Lecanemab has been proposed to target so called Aβ protofibrils. Donanemab is directed against N-terminally modified form of Aβ. These clinical trials collectively suggest that the approach to target Aβ represents an effective strategy for treating AD, particularly in its early stages.  Related Articles | Metrics

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Ambroxol, the cough expectorant with neuroprotective effects Kristin Patzwaldt, Salvador Castaneda-Vega 2024, 19 (11):  2345-2346.  doi: 10.4103/NRR.NRR-D-23-01664 Abstract ( 115 )   PDF (893KB) ( 52 )   Save Ambroxol hydrochloride (2-amino-3,5-dibromo-N-methylbenzylamine hydrochloride) has been used as a mucolytic agent in the treatment of respiratory diseases since the late 1970s. Its effects on mucus membranes such as mucus disruption, increased mucus production, and low toxicity profile were addressed in its original German patent in 1966. These first described properties have kept Ambroxol available worldwide and over the counter in the pharmaceutical market to this day. Since then, many mechanisms of action have been attributed to Ambroxol, including effects on autophagy, anti-inflammation, and neurotrophy. This brief work dives into the latest and most compelling evidence that establishes Ambroxol as a neuroprotective drug in neurodegenerative diseases and highlights its effects on acute neuronal injury. Ambroxol’s ability to penetrate the blood-brain barrier has provided a potential lifeline as recent studies highlight its ability to significantly improve outcomes in acute conditions such as ischemic stroke. These groundbreaking findings, which are yet to be explored in registered clinical trials, showcase Ambroxol as a potential neuroprotective agent that reduces acute injury and preserves brain function (Figure 1). Related Articles | Metrics

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Does HSP27 injection induce glaucoma damage in mice? Stephanie C. Joachim, Sabrina Reinehr 2024, 19 (11):  2347-2348.  doi: 10.4103/NRR.NRR-D-23-01912 Abstract ( 70 )   PDF (1810KB) ( 28 )   Save In a further aging society, excellent eyesight is an integral part of overall well-being and quality of life. Preserving good vision is crucial to maintaining mobility, independence, and mental health. There can be several reasons for visual impairment in elderly people, these include age-related macular degeneration, the leading cause of vision loss among older adults, cataract, glaucoma, diabetic retinopathy, retinal detachment, and others. Related Articles | Metrics

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Oligodendroctyes: the forgotten players of diabetes pathophysiology Juan Antonio López-Villodres, Beatriz García-Díaz 2024, 19 (11):  2349-2350.  doi: 10.4103/NRR.NRR-D-23-01754 Abstract ( 115 )   PDF (2156KB) ( 33 )   Save Oligodendrocytes (OLs), glial cells that provide myelin sheaths to axons in the central nervous system (CNS), have a dual role. First, this myelin fatty cover around the axons protects the nerves and is crucial for the saltatory propagation of action potentials. Second and not less important, OLs provide trophic support to neurons and axons. Thus, OL metabolism is important for OL well-being and the proper accomplishment of their functions, and OL metabolism energetics directly affect the energy metabolism of neighboring neurons. Related Articles | Metrics

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Fish-on-Chips: unveiling neural processing of chemicals in small animals through precise fluidic control Samuel K. H. Sy, Ho Ko 2024, 19 (11):  2351-2353.  doi: 10.4103/1673-5374.392876 Abstract ( 62 )   PDF (872KB) ( 40 )   Save Precise chemical cue presentation alongside advanced brainwide imaging techniques is important to the study of chemosensory processing in animals. Nevertheless, the dynamic nature of chemical-carrying media, such as water or air, poses a significant challenge for delivering highly-controlled chemical flow to an animal subject. Moreover, contact-based cue manipulation and delivery easily shift the position of the animal subject, which is often undesirable for high-quality brain imaging. Additionally, more advanced interfacing tools that align with the diverse range of body part sizes of an animal, ranging from micrometer-scale neurons to meter-long limbs, are much needed. This is particularly crucial when dealing with dimensions that are beyond the reach of conventional experimental tools. Related Articles | Metrics

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Advances in spinal cord injury: insights from non-human primates Gaetan Poulen, Florence E. Perrin 2024, 19 (11):  2354-2364.  doi: 10.4103/NRR.NRR-D-23-01505 Abstract ( 63 )   PDF (1518KB) ( 40 )   Save Spinal cord injury results in significant sensorimotor deficits, currently, there is no curative treatment for the symptoms induced by spinal cord injury. Basic and pre-clinical research on spinal cord injury relies on the development and characterization of appropriate animal models. These models should replicate the symptoms observed in human, allowing for the exploration of functional deficits and investigation into various aspects of physiopathology of spinal cord injury. Non-human primates, due to their close phylogenetic association with humans, share more neuroanatomical, genetic, and physiological similarities with humans than rodents. Therefore, the responses to spinal cord injury in nonhuman primates most likely resemble the responses to traumatism in humans. In this review, we will discuss nonhuman primate models of spinal cord injury, focusing on in vivo assessments, including behavioral tests, magnetic resonance imaging, and electrical activity recordings, as well as ex vivo histological analyses. Additionally, we will present therapeutic strategies developed in non-human primates and discuss the unique specificities of non-human primate models of spinal cord injury. Related Articles | Metrics

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Unveiling DNA methylation in Alzheimer’s disease: a review of array-based human brain studies Victoria Cunha Alves, Eva Carro, Joana Figueiro-Silva 2024, 19 (11):  2365-2376.  doi: 10.4103/1673-5374.393106 Abstract ( 111 )   PDF (798KB) ( 57 )   Save The intricacies of Alzheimer’s disease pathogenesis are being increasingly illuminated by the exploration of epigenetic mechanisms, particularly DNA methylation. This review comprehensively surveys recent human-centered studies that investigate whole genome DNA methylation in Alzheimer’s disease neuropathology. The examination of various brain regions reveals distinctive DNA methylation patterns that associate with the Braak stage and Alzheimer’s disease progression. The entorhinal cortex emerges as a focal point due to its early histological alterations and subsequent impact on downstream regions like the hippocampus. Notably, ANK1 hypermethylation, a protein implicated in neurofibrillary tangle formation, was recurrently identified in the entorhinal cortex. Further, the middle temporal gyrus and prefrontal cortex were shown to exhibit significant hypermethylation of genes like HOXA3, RHBDF2, and MCF2L, potentially influencing neuroinflammatory processes. The complex role of BIN1 in late-onset Alzheimer’s disease is underscored by its association with altered methylation patterns. Despite the disparities across studies, these findings highlight the intricate interplay between epigenetic modifications and Alzheimer’s disease pathology. Future research efforts should address methodological variations, incorporate diverse cohorts, and consider environmental factors to unravel the nuanced epigenetic landscape underlying Alzheimer’s disease progression. Related Articles | Metrics

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Function and dysfunction of GEMIN5: understanding a novel neurodevelopmental disorder Charles H. Nelson, Udai B. Pandey 2024, 19 (11):  2377-2386.  doi: 10.4103/NRR.NRR-D-23-01614 Abstract ( 80 )   PDF (5525KB) ( 127 )   Save The recent identification of a neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) has resulted in an increased interest in GEMIN5, a multifunction RNA-binding protein. As the largest member of the survival motor neuron complex, GEMIN5 plays a key role in the biogenesis of small nuclear ribonucleoproteins while also exhibiting translational regulatory functions as an independent protein. Although many questions remain regarding both the pathogenesis and pathophysiology of this new disorder, considerable progress has been made in the brief time since its discovery. In this review, we examine GEMIN5 within the context of NEDCAM, focusing on the structure, function, and expression of the protein specifically in regard to the disorder itself. Additionally, we explore the current animal models of NEDCAM, as well as potential molecular pathways for treatment and future directions of study. This review provides a comprehensive overview of recent advances in our understanding of this unique member of the survival motor neuron complex. Related Articles | Metrics

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Human brain organoid: trends, evolution, and remaining challenges Minghui Li, Yuhan Yuan, Zongkun Hou, Shilei Hao, Liang Jin, Bochu Wang 2024, 19 (11):  2387-2399.  doi: 10.4103/1673-5374.390972 Abstract ( 307 )   PDF (21720KB) ( 216 )   Save Advanced brain organoids provide promising platforms for deciphering the cellular and molecular processes of human neural development and diseases. Although various studies and reviews have described developments and advancements in brain organoids, few studies have comprehensively summarized and analyzed the global trends in this area of neuroscience. To identify and further facilitate the development of cerebral organoids, we utilized bibliometrics and visualization methods to analyze the global trends and evolution of brain organoids in the last 10 years. First, annual publications, countries/regions, organizations, journals, authors, co-citations, and keywords relating to brain organoids were identified. The hotspots in this field were also systematically identified. Subsequently, current applications for brain organoids in neuroscience, including human neural development, neural disorders, infectious diseases, regenerative medicine, drug discovery, and toxicity assessment studies, are comprehensively discussed. Towards that end, several considerations regarding the current challenges in brain organoid research and future strategies to advance neuroscience will be presented to further promote their application in neurological research. Related Articles | Metrics

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NLRP3/1-mediated pyroptosis: beneficial clues for the development of novel therapies for Alzheimer’s disease Bo Hu, Jiaping Zhang, Jie Huang, Bairu Luo, Xiansi Zeng, Jinjing Jia 2024, 19 (11):  2400-2410.  doi: 10.4103/1673-5374.391311 Abstract ( 244 )   PDF (1686KB) ( 115 )   Save The inflammasome is a multiprotein complex involved in innate immunity that mediates the inflammatory response leading to pyroptosis, which is a lytic, inflammatory form of cell death. There is accumulating evidence that nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3 (NLRP3) inflammasome-mediated microglial pyroptosis and NLRP1 inflammasome-mediated neuronal pyroptosis in the brain are closely associated with the pathogenesis of Alzheimer’s disease. In this review, we summarize the possible pathogenic mechanisms of Alzheimer’s disease, focusing on neuroinflammation. We also describe the structures of NLRP3 and NLRP1 and the role their activation plays in Alzheimer’s disease. Finally, we examine the neuroprotective activity of small-molecule inhibitors, endogenous inhibitor proteins, microRNAs, and natural bioactive molecules that target NLRP3 and NLRP1, based on the rationale that inhibiting NLRP3 and NLRP1 inflammasome-mediated pyroptosis can be an effective therapeutic strategy for Alzheimer’s disease. Related Articles | Metrics

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The physiological role of the unfolded protein response in the nervous system Shuangchan Wu, Wensheng Lin 2024, 19 (11):  2411-2420.  doi: 10.4103/1673-5374.393105 Abstract ( 99 )   PDF (11938KB) ( 22 )   Save The unfolded protein response (UPR) is a cellular stress response pathway activated when the endoplasmic reticulum, a crucial organelle for protein folding and modification, encounters an accumulation of unfolded or misfolded proteins. The UPR aims to restore endoplasmic reticulum homeostasis by enhancing protein folding capacity, reducing protein biosynthesis, and promoting protein degradation. It also plays a pivotal role in coordinating signaling cascades to determine cell fate and function in response to endoplasmic reticulum stress. Recent research has highlighted the significance of the UPR not only in maintaining endoplasmic reticulum homeostasis but also in influencing various physiological processes in the nervous system. Here, we provide an overview of recent findings that underscore the UPR’s involvement in preserving the function and viability of neuronal and myelinating cells under physiological conditions, and highlight the critical role of the UPR in brain development, memory storage, retinal cone development, myelination, and maintenance of myelin thickness. Related Articles | Metrics

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Mechanism of Cu entry into the brain: many unanswered questions Shubhrajit Roy, Svetlana Lutsenko 2024, 19 (11):  2421-2429.  doi: 10.4103/1673-5374.393107 Abstract ( 129 )   PDF (1608KB) ( 91 )   Save Brain tissue requires high amounts of copper (Cu) for its key physiological processes, such as energy production, neurotransmitter synthesis, maturation of neuropeptides, myelination, synaptic plasticity, and radical scavenging. The requirements for Cu in the brain vary depending on specific brain regions, cell types, organism age, and nutritional status. Cu imbalances cause or contribute to several life-threatening neurologic disorders including Menkes disease, Wilson disease, Alzheimer’s disease, Parkinson’s disease, and others. Despite the well-established role of Cu homeostasis in brain development and function, the mechanisms that govern Cu delivery to the brain are not well defined. This review summarizes available information on Cu transfer through the brain barriers and discusses issues that require further research.  Related Articles | Metrics

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Emerging strategies for nerve repair and regeneration in ischemic stroke: neural stem cell therapy Siji Wang, Qianyan He, Yang Qu, Wenjing Yin, Ruoyu Zhao, Xuyutian Wang, Yi Yang, Zhen-Ni Guo 2024, 19 (11):  2430-2443.  doi: 10.4103/1673-5374.391313 Abstract ( 492 )   PDF (2601KB) ( 205 )   Save Ischemic stroke is a major cause of mortality and disability worldwide, with limited treatment options available in clinical practice. The emergence of stem cell therapy has provided new hope to the field of stroke treatment via the restoration of brain neuron function. Exogenous neural stem cells are beneficial not only in cell replacement but also through the bystander effect. Neural stem cells regulate multiple physiological responses, including nerve repair, endogenous regeneration, immune function, and blood-brain barrier permeability, through the secretion of bioactive substances, including extracellular vesicles/exosomes. However, due to the complex microenvironment of ischemic cerebrovascular events and the low survival rate of neural stem cells following transplantation, limitations in the treatment effect remain unresolved. In this paper, we provide a detailed summary of the potential mechanisms of neural stem cell therapy for the treatment of ischemic stroke, review current neural stem cell therapeutic strategies and clinical trial results, and summarize the latest advancements in neural stem cell engineering to improve the survival rate of neural stem cells. We hope that this review could help provide insight into the therapeutic potential of neural stem cells and guide future scientific endeavors on neural stem cells. Related Articles | Metrics

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Cell reprogramming therapy for Parkinson’s disease Wenjing Dong, Shuyi Liu, Shangang Li, Zhengbo Wang 2024, 19 (11):  2444-2455.  doi: 10.4103/1673-5374.390965 Abstract ( 162 )   PDF (1046KB) ( 104 )   Save Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Many studies have been performed based on the supplementation of lost dopaminergic neurons to treat Parkinson’s disease. The initial strategy for cell replacement therapy used human fetal ventral midbrain and human embryonic stem cells to treat Parkinson’s disease, which could substantially alleviate the symptoms of Parkinson’s disease in clinical practice. However, ethical issues and tumor formation were limitations of its clinical application. Induced pluripotent stem cells can be acquired without sacrificing human embryos, which eliminates the huge ethical barriers of human stem cell therapy. Another widely considered neuronal regeneration strategy is to directly reprogram fibroblasts and astrocytes into neurons, without the need for intermediate proliferation states, thus avoiding issues of immune rejection and tumor formation. Both induced pluripotent stem cells and direct reprogramming of lineage cells have shown promising results in the treatment of Parkinson’s disease. However, there are also ethical concerns and the risk of tumor formation that need to be addressed. This review highlights the current application status of cell reprogramming in the treatment of Parkinson’s disease, focusing on the use of induced pluripotent stem cells in cell replacement therapy, including preclinical animal models and progress in clinical research. The review also discusses the advancements in direct reprogramming of lineage cells in the treatment of Parkinson’s disease, as well as the controversy surrounding in vivo reprogramming. These findings suggest that cell reprogramming may hold great promise as a potential strategy for treating Parkinson’s disease. Related Articles | Metrics

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Isoform- and cell-state-specific APOE homeostasis and function Karina Lindner, Anne-Claude Gavin 2024, 19 (11):  2456-2466.  doi: 10.4103/NRR.NRR-D-23-01470 Abstract ( 104 )   PDF (2047KB) ( 47 )   Save Apolipoprotein E is the major lipid transporter in the brain and an important player in neuron-astrocyte metabolic coupling. It ensures the survival of neurons under stressful conditions and hyperactivity by nourishing and detoxifying them. Apolipoprotein E polymorphism, combined with environmental stresses and/or age-related alterations, influences the risk of developing late-onset Alzheimer’s disease. In this review, we discuss our current knowledge of how apolipoprotein E homeostasis, i.e. its synthesis, secretion, degradation, and lipidation, is affected in Alzheimer’s disease. Related Articles | Metrics

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Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer’s disease Yong Tang, Jing Wei, Xiao-Fang Wang, Tao Long, Xiaohong Xiang, Liqun Qu, Xingxia Wang, Chonglin Yu, Xingli Xiao, Xueyuan Hu, Jing Zeng, Qin Xu, Anguo Wu, Jianming Wu, Dalian Qin, Xiaogang Zhou, Betty Yuen-Kwan Law 2024, 19 (11):  2467-2479.  doi: 10.4103/NRR.NRR-D-23-00954 Abstract ( 75 )   PDF (12752KB) ( 47 )   Save Amyloid-beta-induced neuronal cell death contributes to cognitive decline in Alzheimer’s disease. Citri Reticulatae Semen has diverse beneficial effects on neurodegenerative diseases, including Parkinson’s and Huntington’s diseases, however, the effect of Citri Reticulatae Semen on Alzheimer’s disease remains unelucidated. In the current study, the anti-apoptotic and autophagic roles of Citri Reticulatae Semen extract on amyloid-beta-induced apoptosis in PC12 cells were first investigated. Citri Reticulatae Semen extract protected PC12 cells from amyloid-beta-induced apoptosis by attenuating the Bax/Bcl-2 ratio via activation of autophagy. In addition, Citri Reticulatae Semen extract was confirmed to bind amyloid-beta as revealed by biolayer interferometry in vitro, and suppress amyloid-beta-induced pathology such as paralysis, in a transgenic Caenorhabditis elegans in vivo model. Moreover, genetically defective Caenorhabditis elegans further confirmed that the neuroprotective effect of Citri Reticulatae Semen extract was autophagy-dependent. Most importantly, Citri Reticulatae Semen extract was confirmed to improve cognitive impairment, neuronal injury and amyloid-beta burden in 3×Tg Alzheimer’s disease mice. As revealed by both in vitro and in vivo models, these results suggest that Citri Reticulatae Semen extract is a potential natural therapeutic agent for Alzheimer’s disease via its neuroprotective autophagic effects. Related Articles | Metrics

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Cav3.2 channel regulates cerebral ischemia/reperfusion injury: a promising target for intervention Feibiao Dai, Chengyun Hu, Xue Li, Zhetao Zhang, Hongtao Wang Wanjun Zhou, Jiawu Wang, Qingtian Geng, Yongfei Dong, Chaoliang Tang 2024, 19 (11):  2480-2487.  doi: 10.4103/1673-5374.390966 Abstract ( 132 )   PDF (2607KB) ( 79 )   Save Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion injury. Various calcium channels are involved in cerebral ischemia/reperfusion injury. Cav3.2 channel is a main subtype of T-type calcium channels. T-type calcium channel blockers, such as pimozide and mibefradil, have been shown to prevent cerebral ischemia/reperfusion injury-induced brain injury. However, the role of Cav3.2 channels in cerebral ischemia/reperfusion injury remains unclear. Here, in vitro and in vivo models of cerebral ischemia/reperfusion injury were established using middle cerebral artery occlusion in mice and high glucose hypoxia/reoxygenation exposure in primary hippocampal neurons. The results showed that Cav3.2 expression was significantly upregulated in injured hippocampal tissue and primary hippocampal neurons. We further established a Cav3.2 gene-knockout mouse model of cerebral ischemia/reperfusion injury. Cav3.2 knockout markedly reduced infarct volume and brain water content, and alleviated neurological dysfunction after cerebral ischemia/reperfusion injury. Additionally, Cav3.2 knockout attenuated cerebral ischemia/reperfusion injury-induced oxidative stress, inflammatory response, and neuronal apoptosis. In the hippocampus of Cav3.2-knockout mice, calcineurin overexpression offset the beneficial effect of Cav3.2 knockout after cerebral ischemia/reperfusion injury. These findings suggest that the neuroprotective function of Cav3.2 knockout is mediated by calcineurin/nuclear factor of activated T cells 3 signaling. Findings from this study suggest that Cav3.2 could be a promising target for treatment of cerebral ischemia/reperfusion injury. Related Articles | Metrics

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Atherosis-associated lnc_000048 activates PKR to enhance STAT1-mediated polarization of THP-1 macrophages to M1 phenotype Yuanyuan Ding, Yu Sun, Hongyan Wang, Hongqin Zhao, Ruihua Yin, Meng Zhang, Xudong Pan, Xiaoyan Zhu 2024, 19 (11):  2488-2498.  doi: 10.4103/NRR.NRR-D-23-01355 Abstract ( 226 )   PDF (3188KB) ( 65 )   Save Our previous study has demonstrated that lnc_000048 is upregulated in large-artery atherosclerotic stroke and promotes atherosclerosis in ApoE–/– mice. However, little is known about the role of lnc_000048 in classically activated macrophage (M1) polarization. In this study, we established THP-1-derived testing state macrophages (M0), M1 macrophages, and alternately activated macrophages (M2). Real-time fluorescence quantitative PCR was used to verify the expression of marker genes and the expression of lnc_000048 in macrophages. Flow cytometry was used to detect phenotypic proteins (CD11b, CD38, CD80). We generated cell lines with lentivirus-mediated upregulation or downregulation of lnc_000048. Flow cytometry, western blot, and real-time fluorescence quantitative PCR results showed that down-regulation of lnc_000048 reduced M1 macrophage polarization and the inflammation response, while over-expression of lnc_000048 led to the opposite effect. Western blot results indicated that lnc_000048 enhanced the activation of the STAT1 pathway and mediated the M1 macrophage polarization. Moreover, catRAPID prediction, RNA-pull down, and mass spectrometry were used to identify and screen the protein kinase RNA-activated (PKR), then catRAPID and RPIseq were used to predict the binding ability of lnc_000048 to PKR. Immunofluorescence (IF)-RNA fluorescence in situ hybridization (FISH) double labeling was performed to verify the subcellular colocalization of lnc_000048 and PKR in the cytoplasm of M1 macrophage. We speculate that lnc_000048 may form stem-loop structure-specific binding and activate PKR by inducing its phosphorylation, leading to activation of STAT1 phosphorylation and thereby enhancing STAT1 pathway-mediated polarization of THP-1 macrophages to M1 and inflammatory factor expression. Taken together, these results reveal that the lnc_000048/PKR/STAT1 axis plays a crucial role in the polarization of M1 macrophages and may be a novel therapeutic target for atherosclerosis alleviation in stroke. Related Articles | Metrics

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Ruxolitinib improves the inflammatory microenvironment, restores glutamate homeostasis, and promotes functional recovery after spinal cord injury Jiang Cao, Xiao Yu, Jingcheng Liu, Jiaju Fu, Binyu Wang, Chaoqin Wu, Sheng Zhang, Hongtao Chen, Zi Wang, Yinyang Xu, Tao Sui, Jie Chang, Xiaojian Cao 2024, 19 (11):  2499-2512.  doi: 10.4103/NRR.NRR-D-23-01863 Abstract ( 189 )   PDF (12590KB) ( 129 )   Save The inflammatory microenvironment and neurotoxicity can hinder neuronal regeneration and functional recovery after spinal cord injury. Ruxolitinib, a JAK-STAT inhibitor, exhibits effectiveness in autoimmune diseases, arthritis, and managing inflammatory cytokine storms. Although studies have shown the neuroprotective potential of ruxolitinib in neurological trauma, the exact mechanism by which it enhances functional recovery after spinal cord injury, particularly its effect on astrocytes, remains unclear. To address this gap, we established a mouse model of T10 spinal cord contusion and found that ruxolitinib effectively improved hindlimb motor function and reduced the area of spinal cord injury. Transcriptome sequencing analysis showed that ruxolitinib alleviated inflammation and immune response after spinal cord injury, restored EAAT2 expression, reduced glutamate levels, and alleviated excitatory toxicity. Furthermore, ruxolitinib inhibited the phosphorylation of JAK2 and STAT3 in the injured spinal cord and decreased the phosphorylation level of nuclear factor kappa-B and the expression of inflammatory factors interleukin-1β, interleukin-6, and tumor necrosis factor-α. Additionally, in glutamate-induced excitotoxicity astrocytes, ruxolitinib restored EAAT2 expression and increased glutamate uptake by inhibiting the activation of STAT3, thereby reducing glutamate-induced neurotoxicity, calcium influx, oxidative stress, and cell apoptosis, and increasing the complexity of dendritic branching. Collectively, these results indicate that ruxolitinib restores glutamate homeostasis by rescuing the expression of EAAT2 in astrocytes, reduces neurotoxicity, and effectively alleviates inflammatory and immune responses after spinal cord injury, thereby promoting functional recovery after spinal cord injury. Related Articles | Metrics

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OSMR is a potential driver of inflammation in amyotrophic lateral sclerosis Wenzhi Chen, Shishi Jiang, Shu Li, Cheng Li, Renshi Xu 2024, 19 (11):  2513-2521.  doi: 10.4103/1673-5374.391309 Abstract ( 104 )   PDF (4441KB) ( 51 )   Save Amyotrophic lateral sclerosis is a neurodegenerative disease, and the molecular mechanism underlying its pathology remains poorly understood. However, inflammation is known to play an important role in the development of this condition. To identify driver genes that affect the inflammatory response in amyotrophic lateral sclerosis, as well as potential treatment targets, it is crucial to analyze brain tissue samples from patients with both sporadic amyotrophic lateral sclerosis and C9orf72-related amyotrophic lateral sclerosis. Therefore, in this study we used a network-driven gene analysis tool, NetBID2.0, which is based on SJARACNe, a scalable algorithm for the reconstruction of accurate cellular networks, to experimentally analyze sequencing data from patients with sporadic amyotrophic lateral sclerosis. The results showed that the OSMR gene is pathogenic in amyotrophic lateral sclerosis and participates in the progression of amyotrophic lateral sclerosis by mediating the neuroinflammatory response. Furthermore, there were differences in OSMR activity and expression between patients with sporadic amyotrophic lateral sclerosis and those with C9orf72-related amyotrophic lateral sclerosis. These findings suggest that OSMR may be a diagnostic and prognostic marker for amyotrophic lateral sclerosis. Related Articles | Metrics

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Single-cell RNA sequencing analysis of the retina under acute high intraocular pressure Shaojun Wang, Siti Tong, Xin Jin, Na Li, Pingxiu Dang, Yang Sui, Ying Liu, Dajiang Wang 2024, 19 (11):  2522-2531.  doi: 10.4103/1673-5374.389363 Abstract ( 138 )   PDF (3480KB) ( 77 )   Save High intraocular pressure causes retinal ganglion cell injury in primary and secondary glaucoma diseases, yet the molecular landscape characteristics of retinal cells under high intraocular pressure remain unknown. Rat models of acute hypertension ocular pressure were established by injection of cross-linked hyaluronic acid hydrogel (Healaflow®). Single-cell RNA sequencing was then used to describe the cellular composition and molecular profile of the retina following high intraocular pressure. Our results identified a total of 12 cell types, namely retinal pigment epithelial cells, rod-photoreceptor cells, bipolar cells, Müller cells, microglia, cone-photoreceptor cells, retinal ganglion cells, endothelial cells, retinal progenitor cells, oligodendrocytes, pericytes, and fibroblasts. The single-cell RNA sequencing analysis of the retina under acute high intraocular pressure revealed obvious changes in the proportions of various retinal cells, with ganglion cells decreased by 23%. Hematoxylin and eosin staining and TUNEL staining confirmed the damage to retinal ganglion cells under high intraocular pressure. We extracted data from retinal ganglion cells and analyzed the retinal ganglion cell cluster with the most distinct expression. We found upregulation of the B3gat2 gene, which is associated with neuronal migration and adhesion, and downregulation of the Tsc22d gene, which participates in inhibition of inflammation. This study is the first to reveal molecular changes and intercellular interactions in the retina under high intraocular pressure. These data contribute to understanding of the molecular mechanism of retinal injury induced by high intraocular pressure and will benefit the development of novel therapies. Related Articles | Metrics

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Neuroprotective effects of G9a inhibition through modulation of peroxisome-proliferator activator receptor gamma-dependent pathways by miR-128 Aina Bellver-Sanchis, Pedro A. Ávila-López, Iva Tic, David Valle-García, Marta Ribalta-Vilella, Luis Labrador, Deb Ranjan Banerjee, Ana Guerrero, Gemma Casadesus, Coralie Poulard, Mercè Pallàs, Christian Griñán-Ferré 2024, 19 (11):  2532-2542.  doi: 10.4103/1673-5374.393102 Abstract ( 142 )   PDF (6890KB) ( 43 )   Save Dysregulation of G9a, a histone-lysine N-methyltransferase, has been observed in Alzheimer’s disease and has been correlated with increased levels of chronic inflammation and oxidative stress. Likewise, microRNAs are involved in many biological processes and diseases playing a key role in pathogenesis, especially in multifactorial diseases such as Alzheimer’s disease. Therefore, our aim has been to provide partial insights into the interconnection between G9a, microRNAs, oxidative stress, and neuroinflammation. To better understand the biology of G9a, we compared the global microRNA expression between senescence-accelerated mouse-prone 8 (SAMP8) control mice and SAMP8 treated with G9a inhibitor UNC0642. We found a downregulation of miR-128 after a G9a inhibition treatment, which interestingly binds to the 3′ untranslated region (3′-UTR) of peroxisome-proliferator activator receptor γ (PPARG) mRNA. Accordingly, Pparg gene expression levels were higher in the SAMP8 group treated with G9a inhibitor than in the SAMP8 control group. We also observed modulation of oxidative stress responses might be mainly driven Pparg after G9a inhibitor. To confirm these antioxidant effects, we treated primary neuron cell cultures with hydrogen peroxide as an oxidative insult. In this setting, treatment with G9a inhibitor increases both cell survival and antioxidant enzymes. Moreover, up-regulation of PPARγ by G9a inhibitor could also increase the expression of genes involved in DNA damage responses and apoptosis. In addition, we also described that the PPARγ/AMPK axis partially explains the regulation of autophagy markers expression. Finally, PPARγ/GADD45α potentially contributes to enhancing synaptic plasticity and neurogenesis after G9a inhibition. Altogether, we propose that pharmacological inhibition of G9a leads to a neuroprotective effect that could be due, at least in part, by the modulation of PPARγ-dependent pathways by miR-128. Related Articles | Metrics

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Optimal transcorneal electrical stimulation parameters for preserving photoreceptors in a mouse model of retinitis pigmentosa Sam Enayati, Karen Chang, Anton Lennikov, Menglu Yang, Cherin Lee, Ajay Ashok, Farris Elzaridi, Christina Yen, Kasim Gunes, Jia Xie, Kin-Sang Cho, Tor Paaske Utheim, Dong Feng Chen 2024, 19 (11):  2543-2552.  doi: 10.4103/1673-5374.392888 Abstract ( 149 )   PDF (9860KB) ( 35 )   Save Retinitis pigmentosa is a hereditary retinal disease that affects rod and cone photoreceptors, leading to progressive photoreceptor loss. Previous research supports the beneficial effect of electrical stimulation on photoreceptor survival. This study aims to identify the most effective electrical stimulation parameters and functional advantages of transcorneal electrical stimulation (tcES) in mice affected by inherited retinal degeneration. Additionally, the study seeked to analyze the electric field that reaches the retina in both eyes in mice and post-mortem humans. In this study, we recorded waveforms and voltages directed to the retina during transcorneal electrical stimulation in C57BL/6J mice using an intraocular needle probe with rectangular, sine, and ramp waveforms. To investigate the functional effects of electrical stimulation on photoreceptors, we used human retinal explant cultures and rhodopsin knockout (Rho–/–) mice, demonstrating progressive photoreceptor degeneration with age. Human retinal explants isolated from the donors’ eyes were then subjected to electrical stimulation and cultured for 48 hours to simulate the neurodegenerative environment in vitro. Photoreceptor density was evaluated by rhodopsin immunolabeling. In vivo Rho–/– mice were subjected to two 5-day series of daily transcorneal electrical stimulation using rectangular and ramp waveforms. Retinal function and visual perception of mice were evaluated by electroretinography and optomotor response (OMR), respectively. Immunolabeling was used to assess the morphological and biochemical changes of the photoreceptor and bipolar cells in mouse retinas. Oscilloscope recordings indicated effective delivery of rectangular, sine, and ramp waveforms to the retina by transcorneal electrical stimulation, of which the ramp waveform required the lowest voltage. Evaluation of the total conductive resistance of the post-mortem human compared to the mouse eyes indicated higher cornea-to-retina resistance in human eyes. The temperature recordings during and after electrical stimulation indicated no significant temperature change in vivo and only a subtle temperature increase in vitro (~0.5–1.5°C). Electrical stimulation increased photoreceptor survival in human retinal explant cultures, particularly at the ramp waveform. Transcorneal electrical stimulation (rectangular + ramp) waveforms significantly improved the survival and function of S and M-cones and enhanced visual acuity based on the optomotor response results. Histology and immunolabeling demonstrated increased photoreceptor survival, improved outer nuclear layer thickness, and increased bipolar cell sprouting in Rho–/– mice. These results indicate that transcorneal electrical stimulation effectively delivers the electrical field to the retina, improves photoreceptor survival in both human and mouse retinas, and increases visual function in Rho–/– mice. Combined rectangular and ramp waveform stimulation can promote photoreceptor survival in a minimally invasive fashion.  Related Articles | Metrics