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15 August 2022, Volume 17 Issue 8 Previous Issue   

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Estrogen rapid effects: a window of opportunity for the aging brain? Ivanny Marchant, Jana Stojanova, Lilian Acevedo, Pablo Olivero 2022, 17 (8):  1629-1632.  doi: 10.4103/1673-5374.332121 Abstract ( 241 )   PDF (462KB) ( 140 )   Save Estrogen produces several beneficial effects in healthy neurological tissues and exhibits cardioprotective effects. Hormone therapy has been widely used to treat menopausal estrogen deficiency for more than 80 years. Despite high initial expectations of cardioprotective effects, there has been substantial distrust following important randomized clinical trials, such as the Women’s Health Initiative. Subsequently, the timing of treatment in relation to the onset of menopause came under consideration and led to the proposal of the timing hypothesis, that early initial treatment is important, and benefits are lost as the timing since menopause becomes prolonged. Subsequent analyses of the Women’s Health Initiative data, together with more recent data from randomized and observational trials, consistently show reductions in coronary heart disease and mortality in younger menopausal women. Regarding cognitive function, the timing hypothesis is consistent with observations from basic and animal studies. There is some clinical evidence to support the benefits of hormonal therapy in this context, though skepticism remains due to the paucity of clinical trials of substantial length in younger menopausal women. It is likely that the effects of estrogens on cognitive performance are due to rapid mechanisms, including mechanisms that influence Ca2+ homeostasis dynamics, provide protection in a hostile environment and reduce inflammatory signals from neural tissues. In the future, inflammatory profiles accounting for early signs of pathological inflammation might help identify the ‘window of opportunity’ to use estrogen therapy for successful cognitive protection. Related Articles | Metrics

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Motor neuron replacement therapy for amyotrophic lateral sclerosis Bochao Liu, Mo Li, Lingyan Zhang, Zhiguo Chen, Paul Lu 2022, 17 (8):  1633-1639.  doi: 10.4103/1673-5374.332123 Abstract ( 174 )   PDF (12757KB) ( 148 )   Save Amyotrophic lateral sclerosis is a motor neuron degenerative disease that is also known as Lou Gehrig’s disease in the United States, Charcot’s disease in France, and motor neuron disease in the UK. The loss of motor neurons causes muscle wasting, paralysis, and eventually death, which is commonly related to respiratory failure, within 3–5 years after onset of the disease. Although there are a limited number of drugs approved for amyotrophic lateral sclerosis, they have had little success at treating the associated symptoms, and they cannot reverse the course of motor neuron degeneration. Thus, there is still a lack of effective treatment for this debilitating neurodegenerative disorder. Stem cell therapy for amyotrophic lateral sclerosis is a very attractive strategy for both basic and clinical researchers, particularly as transplanted stem cells and stem cell-derived neural progenitor/precursor cells can protect endogenous motor neurons and directly replace the lost or dying motor neurons. Stem cell therapies may also be able to re-establish the motor control of voluntary muscles. Here, we review the recent progress in the use of neural stem cells and neural progenitor cells for the treatment of amyotrophic lateral sclerosis. We focus on MN progenitor cells derived from fetal central nervous system tissue, embryonic stem cells, and induced pluripotent stem cells. In our recent studies, we found that transplanted human induced pluripotent stem cell-derived motor neuron progenitors survive well, differentiate into motor neurons, and extend axons into the host white matter, not only in the rostrocaudal direction, but also along motor axon tracts towards the ventral roots in the immunodeficient rat spinal cord. Furthermore, the significant motor axonal extension after neural progenitor cell transplantation in amyotrophic lateral sclerosis models demonstrates that motor neuron replacement therapy could be a promising therapeutic strategy for amyotrophic lateral sclerosis, particularly as a variety of stem cell derivatives, including induced pluripotent stem cells, are being considered for clinical trials for various diseases. Related Articles | Metrics

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Calorie restriction or dietary restriction: how far they can protect the brain against neurodegenerative diseases? Tayana Silva de Carvalho 2022, 17 (8):  1640-1644.  doi: 10.4103/1673-5374.332126 Abstract ( 297 )   PDF (448KB) ( 74 )   Save Finding the correct nutritional intervention is one of the biggest challenges in treating patients with neurodegenerative diseases. In general, these patients develop strong metabolic alterations, resulting in lower treatment efficacy and higher mortality rates. However, there are still many open questions regarding the effectiveness of dietary interventions in neurodiseases. Some studies have shown that a reduction in calorie intake activates key pathways that might be important for preventing or slowing down the progression of such diseases. However, it is still unclear whether these neuroprotective effects are associated with an overall reduction in calories (hypocaloric diet) or a specific nutrient restriction (diet restriction). Therefore, here we discuss how commonly or differently hypocaloric and restricted diets modulate signaling pathways and how these changes can protect the brain against neurodegenerative diseases. Related Articles | Metrics

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Phosphorylated tau as a toxic agent in synaptic mitochondria: implications in aging and Alzheimer’s disease Angie K. Torres, Bastián I. Rivera, Catalina M. Polanco, Claudia Jara, Cheril Tapia-Rojas 2022, 17 (8):  1645-1651.  doi: 10.4103/1673-5374.332125 Abstract ( 261 )   PDF (1283KB) ( 111 )   Save During normal aging, there is a decline in all physiological functions in the organism. One of the most affected organs is the brain, where neurons lose their proper synaptic function leading to cognitive impairment. Aging is one of the main risk factors for the development of neurodegenerative diseases, such as Alzheimer’s disease. One of the main responsible factors for synaptic dysfunction in aging and neurodegenerative diseases is the accumulation of abnormal proteins forming aggregates. The most studied brain aggregates are the senile plaques, formed by Aβ peptide; however, the aggregates formed by phosphorylated tau protein have gained relevance in the last years by their toxicity. It is reported that neurons undergo severe mitochondrial dysfunction with age, with a decrease in adenosine 5′-triphosphate production, loss of the mitochondrial membrane potential, redox imbalance, impaired mitophagy, and loss of calcium buffer capacity. Interestingly, abnormal tau protein interacts with several mitochondrial proteins, suggesting that it could induce mitochondrial dysfunction. Nevertheless, whether tau-mediated mitochondrial dysfunction occurs indirectly or directly is still unknown. A recent study of our laboratory shows that phosphorylated tau at Ser396/404 (known as PHF-1), an epitope commonly related to pathology, accumulates inside mitochondria during normal aging. This accumulation occurs preferentially in synaptic mitochondria, which suggests that it may contribute to the synaptic failure and cognitive impairment seen in aged individuals. Here, we review the main tau modifications promoting mitochondrial dysfunction, and the possible mechanism involved. Also, we discuss the evidence that supports the possibility that phosphorylated tau accumulation in synaptic mitochondria promotes synaptic and cognitive impairment in aging. Finally, we show evidence and argue about the presence of phosphorylated tau PHF-1 inside mitochondria in Alzheimer’s disease, which could be considered as an early event in the neurodegenerative process. Thus, phosphorylated tau PHF-1 inside the mitochondria could be considered such a potential therapeutic target to prevent or attenuate age-related cognitive impairment. Related Articles | Metrics

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Parkinson’s disease and diabetes mellitus: common mechanisms and treatment repurposing Carmen M. Labandeira, Arturo Fraga-Bau, David Arias Ron, Elena Alvarez-Rodriguez, Pablo Vicente-Alba, Javier Lago-Garma, Ana I. Rodriguez-Perez 2022, 17 (8):  1652-1658.  doi: 10.4103/1673-5374.332122 Abstract ( 363 )   PDF (6338KB) ( 165 )   Save In the last decade, attention has become greater to the relationship between neurodegeneration and abnormal insulin signaling in the central nervous system, as insulin in the brain is implicated in neuronal survival, plasticity, oxidative stress and neuroinflammation. Diabetes mellitus and Parkinson’s disease are both aging-associated diseases that are turning into epidemics worldwide. Diabetes mellitus and insulin resistance not only increase the possibility of developing Parkinson’s disease but can also determine the prognosis and progression of Parkinsonian symptoms. Today, there are no available curative or disease modifying treatments for Parkinson’s disease, but the role of insulin and antidiabetic medications in neurodegeneration opens a door to treatment repurposing to fight against Parkinson’s disease, both in diabetic and nondiabetic Parkinsonian patients. Furthermore, it is essential to comprehend how a frequent and treatable disease such as diabetes can influence the progression of neurodegeneration in a challenging disease such as Parkinson’s disease. Here, we review the present evidence on the connection between Parkinson’s disease and diabetes and the consequential implications of the existing antidiabetic molecules in the severity and development of Parkinsonism, with a particular focus on glucagon-like peptide-1 receptor agonists. Related Articles | Metrics

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Astrocyte in prion disease: a double-edged sword Waqas Tahir, Simrika Thapa, Hermann M. Schatzl 2022, 17 (8):  1659-1665.  doi: 10.4103/1673-5374.332202 Abstract ( 190 )   PDF (1625KB) ( 116 )   Save Prion diseases are infectious protein misfolding disorders of the central nervous system that result from misfolding of the cellular prion protein (PrPC) into the pathologic isoform PrPSc. Pathologic hallmarks of prion disease are depositions of pathological prion protein PrPSc, neuronal loss, spongiform degeneration and astrogliosis in the brain. Prion diseases affect human and animals, there is no effective therapy, and they invariably remain fatal. For a long time, neuronal loss was considered the sole reason for neurodegeneration in prion pathogenesis, and the contribution of non-neuronal cells like microglia and astrocytes was considered less important. Recent evidence suggests that neurodegeneration during prion pathogenesis is a consequence of a complex interplay between neuronal and non-neuronal cells in the brain, but the exact role of these non-neuronal cells during prion pathology is still elusive. Astrocytes are non-neuronal cells that regulate brain homeostasis under physiological conditions. However, astrocytes can deposit PrPSc aggregates and propagate prions in prion-infected brains. Additionally, sub-populations of reactive astrocytes that include neurotrophic and neurotoxic species have been identified, differentially expressed in the brain during prion infection. Revealing the exact role of astrocytes in prion disease is hampered by the lack of in vitro models of prion-infected astrocytes. Recently, we established a murine astrocyte cell line persistently infected with mouse-adapted prions, and showed how such astrocytes differentially process various prion strains. Considering the complexity of the role of astrocytes in prion pathogenesis, we need more in vitro and in vivo models for exploring the contribution of sub-populations of reactive astrocytes, their differential regulation of signaling cascades, and the interaction with neurons and microglia during prion pathogenesis. This will help to establish novel in vivo models and define new therapeutic targets against prion diseases. In this review, we will discuss the complex role of astrocytes in prion disease, the existing experimental resources, the challenges to analyze the contribution of astrocytes in prion disease pathogenesis, and future strategies to improve the understanding of their role in prion disease. Related Articles | Metrics

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Amyloid-beta peptide and tau protein crosstalk in Alzheimer’s disease Alejandro R. Roda, Gabriel Serra-Mir, Laia Montoliu-Gaya, Lidia Tiessler, Sandra Villegas 2022, 17 (8):  1666-1674.  doi: 10.4103/1673-5374.332127 Abstract ( 343 )   PDF (3851KB) ( 173 )   Save Alzheimer’s disease is a neurodegenerative disease that accounts for most of the 50-million dementia cases worldwide in 2018. A large amount of evidence supports the amyloid cascade hypothesis, which states that amyloid-beta accumulation triggers tau hyperphosphorylation and aggregation in form of neurofibrillary tangles, and these aggregates lead to inflammation, synaptic impairment, neuronal loss, and thus to cognitive decline and behavioral abnormalities. The poor correlation found between cognitive decline and amyloid plaques, have led the scientific community to question whether amyloid-beta accumulation is actually triggering neurodegeneration in Alzheimer’s disease. The occurrence of tau neurofibrillary tangles better correlates to neuronal loss and clinical symptoms and, although amyloid-beta may initiate the cascade of events, tau impairment is likely the effector molecule of neurodegeneration. Recently, it has been shown that amyloid-beta and tau cooperatively work to impair transcription of genes involved in synaptic function and, more importantly, that downregulation of tau partially reverses transcriptional perturbations. Despite mounting evidence points to an interplay between amyloid-beta and tau, some factors could independently affect both pathologies. Thus, the dual pathway hypothesis, which states that there are common upstream triggers causing both amyloid-beta and tau abnormalities has been proposed. Among others, the immune system seems to be strongly involved in amyloid-beta and tau pathologies. Other factors, as the apolipoprotein E ε4 isoform has been suggested to act as a link between amyloid-beta and tau hyperphosphorylation. Interestingly, amyloid-beta-immunotherapy reduces not only amyloid-beta but also tau levels in animal models and in clinical trials. Likewise, it has been shown that tau-immunotherapy also reduces amyloid-beta levels. Thus, even though amyloid-beta immunotherapy is more advanced than tau-immunotherapy, combined amyloid-beta and tau-directed therapies at early stages of the disease have recently been proposed as a strategy to stop the progression of Alzheimer’s disease. Related Articles | Metrics

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Phytochemicals as inhibitors of tumor necrosis factor alpha and neuroinflammatory responses in neurodegenerative diseases Fatemeh Zahedipour, Seyede Atefe Hosseini, Neil C. Henney, George E. Barreto, Amirhossein Sahebkar 2022, 17 (8):  1675-1684.  doi: 10.4103/1673-5374.332128 Abstract ( 297 )   PDF (689KB) ( 140 )   Save Inflammatory processes and proinflammatory cytokines have a key role in the cellular processes of neurodegenerative diseases and are linked to the pathogenesis of functional and mental health disorders. Tumor necrosis factor alpha has been reported to play a major role in the central nervous system in Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis and many other neurodegenerative diseases. Therefore, a potent proinflammatory/proapoptotic tumor necrosis factor alpha could be a strong candidate for targeted therapy. Plant derivatives have now become promising candidates as therapeutic agents because of their antioxidant and chemical characteristics, and anti-inflammatory features. Recently, phytochemicals including flavonoids, terpenoids, alkaloids, and lignans have generated interest as tumor necrosis factor alpha inhibitor candidates for a number of diseases involving inflammation within the nervous system. In this review, we discuss how phytochemicals as tumor necrosis factor alpha inhibitors are a therapeutic strategy targeting neurodegeneration. Related Articles | Metrics

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Construction and imaging of a neurovascular unit model Taiwei Dong, Min Li, Feng Gao, Peifeng Wei, Jian Wang 2022, 17 (8):  1685-1694.  doi: 10.4103/1673-5374.332131 Abstract ( 389 )   PDF (1447KB) ( 239 )   Save In 2001, the concept of the neurovascular unit was introduced at the Stroke Progress Review Group meeting. The neurovascular unit is an important element of the health and disease status of blood vessels and nerves in the central nervous system. Since then, the neurovascular unit has attracted increasing interest from research teams, who have contributed greatly to the prevention, treatment, and prognosis of stroke and neurodegenerative diseases. However, additional research is needed to establish an efficient, low-cost, and low-energy in vitro model of the neurovascular unit, as well as enable noninvasive observation of neurovascular units in vivo and in vitro. In this review, we first summarize the composition of neurovascular units, then investigate the efficacy of different types of stem cells and cell culture methods in the construction of neurovascular unit models, and finally assess the progress of imaging methods used to observe neurovascular units in recent years and their positive role in the monitoring and investigation of the mechanisms of a variety of central nervous system diseases. Related Articles | Metrics

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The brain as a source and a target of prolactin in mammals Ana R. Costa-Brito, Isabel Gonçalves, Cecília R. A. Santos 2022, 17 (8):  1695-1702.  doi: 10.4103/1673-5374.332124 Abstract ( 257 )   PDF (1538KB) ( 115 )   Save Prolactin is a polypeptide hormone associated with an extensive variety of biological functions. Among the roles of prolactin in vertebrates, some were preserved throughout evolution. This is the case of its function in the brain, where prolactin receptors, are expressed in different structures of the central nervous system. In the brain, prolactin actions are principally associated with reproduction and parental behavior, and involves the modulation of adult neurogenesis, neuroprotection, and neuroplasticity, especially during pregnancy, thereby preparing the brain to parenthood. Prolactin is mainly produced by specialized cells in the anterior pituitary gland. However, during vertebrate evolution many other extrapituitary tissues do also produce prolactin, like the immune system, endothelial cells, reproductive structures and in several regions of the brain. This review summarizes the relevance of prolactin for brain function, the sources of prolactin in the central nervous system, as well as its local production and secretion. A highlight on the impact of prolactin in human neurological diseases is also provided. Related Articles | Metrics

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Elevated intraspinal pressure in traumatic spinal cord injury is a promising therapeutic target Chao-Hua Yang, Zheng-Xue Quan, Gao-Ju Wang, Tao He, Zhi-Yu Chen, Qiao-Chu Li, Jin Yang, Qing Wang 2022, 17 (8):  1703-1710.  doi: 10.4103/1673-5374.332203 Abstract ( 349 )   PDF (1008KB) ( 68 )   Save The currently recommended management for acute traumatic spinal cord injury aims to reduce the incidence of secondary injury and promote functional recovery. Elevated intraspinal pressure (ISP) likely plays an important role in the processes involved in secondary spinal cord injury, and should not be overlooked. However, the factors and detailed time course contributing to elevated ISP and its impact on pathophysiology after traumatic spinal cord injury have not been reviewed in the literature. Here, we review the etiology and progression of elevated ISP, as well as potential therapeutic measures that target elevated ISP. Elevated ISP is a time-dependent process that is mainly caused by hemorrhage, edema, and blood-spinal cord barrier destruction and peaks at 3 days after traumatic spinal cord injury. Duraplasty and hypertonic saline may be promising treatments for reducing ISP within this time window. Other potential treatments such as decompression, spinal cord incision, hemostasis, and methylprednisolone treatment require further validation. Related Articles | Metrics

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Myeloperoxidase: a new target for the treatment of stroke? Yun-Chang Wang, Yu-Bao Lu, Xiao-Lan Huang, Yong-Feng Lao, Lu Zhang, Jun Yang, Mei Shi, Hai-Long Ma, Ya-Wen Pan, Yi-Nian Zhang 2022, 17 (8):  1711-1716.  doi: 10.4103/1673-5374.332130 Abstract ( 234 )   PDF (2452KB) ( 139 )   Save Myeloperoxidase is an important inflammatory factor in the myeloid system, primarily expressed in neutrophils and microglia. Myeloperoxidase and its active products participate in the occurrence and development of hemorrhagic and ischemic stroke, including damage to the blood-brain barrier and brain. As a specific inflammatory marker, myeloperoxidase can be used in the evaluation of vascular disease occurrence and development in stroke, and a large amount of experimental and clinical data has indicated that the inhibition or lack of myeloperoxidase has positive impacts on stroke prognosis. Many studies have also shown that there is a correlation between the overexpression of myeloperoxidase and the risk of stroke. The occurrence of stroke not only refers to the first occurrence but also includes recurrence. Therefore, myeloperoxidase is significant for the clinical evaluation and prognosis of stroke. This paper reviews the potential role played by myeloperoxidase in the development of vascular injury and secondary brain injury after stroke and explores the effects of inhibiting myeloperoxidase on stroke prognosis. This paper also analyzes the significance of myeloperoxidase etiology in the occurrence and development of stroke and discusses whether myeloperoxidase can be used as a target for the treatment and prediction of stroke. Related Articles | Metrics

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Small interfering RNAs based therapies for intracerebral hemorrhage: challenges and progress in drug delivery systems Daniyah A. Almarghalani, Sai H.S. Boddu, Mohammad Ali, Akhila Kondaka, Devin Ta, Rayyan A. Shah, Zahoor A. Shah 2022, 17 (8):  1717-1725.  doi: 10.4103/1673-5374.332129 Abstract ( 161 )   PDF (1175KB) ( 105 )   Save Intracerebral hemorrhage (ICH) is a subtype of stroke associated with higher rates of mortality. Currently, no effective drug treatment is available for ICH. The molecular pathways following ICH are complicated and diverse. Nucleic acid therapeutics such as gene knockdown by small interfering RNAs (siRNAs) have been developed in recent years to modulate ICH’s destructive pathways and mitigate its outcomes. However, siRNAs delivery to the central nervous system is challenging and faces many roadblocks. Existing barriers to systemic delivery of siRNA limit the use of naked siRNA; therefore, siRNA-vectors developed to protect and deliver these therapies into the specific-target areas of the brain, or cell types seem quite promising. Efficient delivery of siRNA via nanoparticles emerged as a viable and effective alternative therapeutic tool for central nervous system-related diseases. This review discusses the obstacles to siRNA delivery, including the advantages and disadvantages of viral and nonviral vectors. Additionally, we provide a comprehensive overview of recent progress in nanotherapeutics areas, primarily focusing on the delivery system of siRNA for ICH treatment. Related Articles | Metrics

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Monodelphis domestica: a new source of mammalian primary neurons in vitro Jelena Ban, Miranda Mladinic 2022, 17 (8):  1726-1727.  doi: 10.4103/1673-5374.332139 Abstract ( 114 )   PDF (524KB) ( 63 )   Save In vitro models have tremendously revolutionized cell biology and biomedical research, reducing the need for in vivo experiments, as well as offering the simplified models for easier investigations at molecular and cellular level (for example genetic manipulations, electrophysiological measurements, drug screening etc.). However, the major challenge is to develop long-surviving in vitro preparations of post-mitotic cells such as neurons or cardiocytes. To overcome the problem of neuronal inability to proliferate, the immortalized cell lines derived from neuronal tumors have been prepared. Such secondary neuronal cultures are restricted to neuroblastoma-like cells, but their biological relevance is often questionable due to genetic drift and lack of mature, differentiated neuronal phenotypes, which makes primary cultures the better choice. Mammalian central nervous system (CNS) in vitro primary cell cultures are mostly prepared from the late embryonic or early postnatal mice and rats. Other mammalian species have been less used, meaning that inter-species diversity is not sufficiently investigated and that the additional comparative analyses are required to avoid misinterpretations in translating the knowledge to humans (Bonfanti and Peretto, 2011). Related Articles | Metrics

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Vascular inflammation in the central nervous system Xinying Guo, Zhen Zhao 2022, 17 (8):  1728-1730.  doi: 10.4103/1673-5374.332140 Abstract ( 158 )   PDF (562KB) ( 70 )   Save Vasculature is the interface between tissue and circulation. It consists of endothelial cells, mural cells including vascular smooth muscle cells and pericytes, and other perivascular cells including macrophages and fibroblasts (Sweeney et al., 2019). The vascular system not only delivers oxygen and nutrients, but also shuttles the immune cells around. As the first line of defense, the vascular system also senses the changes in surrounding tissue, particularly inflammation. Vascular inflammation can occur in blood vessels of all sizes in any organ. It has a complex etiology, including infections such as coronavirus disease-19 (COVID-19), and chronic conditions such as diabetes, hypertension and neurodegenerative diseases (Hanafi et al., 2020). Excessive vascular inflammation is clinically known as vasculitis, diagnosed by blood test, imaging and biopsy. Vasculitis not only thickens the blood vessel wall, causing blood flow reduction and insufficient delivery of oxygen and nutrients, but also triggers inflammatory responses in secondary sites, or even the whole body. Related Articles | Metrics

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Proper progression of neurogenesis relies on a defined pattern of SUMO-modified proteins Mario García-Domínguez 2022, 17 (8):  1731-1732.  doi: 10.4103/1673-5374.332134 Abstract ( 127 )   PDF (1618KB) ( 87 )   Save Neurogenesis is a complex process involving the orchestration of many transcription factors and other proteins. Fine regulation of their activities is crucial for proper progression of neurogenesis. A few decades ago, covalent attachment of Small Ubiquitin-like MOdifier (SUMO) to other proteins was revealed as a major regulator of protein activities, constituting an essential posttranslational modification system in vertebrates. Since then, hundreds of proteins have been shown to be targets of SUMO, which is implicated in controlling many relevant processes in eukaryotic cells. These include the development and function of the nervous system, with SUMO tightly linked to synapsis and to neurodegenerative diseases (Yau et al., 2020). The SUMO protease SENP7 has been involved in neurogenesis (Juárez-Vicente et al., 2016), while sumoylation of BRAF35, a subunit of the LSD1 histone demethylase complex, assures the undifferentiated state of neural progenitors (Ceballos-Chávez et al., 2012). In addition, increased sumoylation in mouse brain-derived neural stem cells results in enhanced neuronal differentiation (Bernstock et al., 2019). However, in general, the implication of SUMO in neuronal differentiation and nervous system development has been poorly studied. We have recently developed a proteomic study aimed at identifying SUMO targets associated either with proliferation or with neuronal differentiation conditions, which has highlighted the relevance of SUMO modification for proper progression of neurogenesis. Here, we discuss our recent results, present specific SUMO targets that are key to the process, and indicate future research directions to uncover the molecular mechanisms underlying SUMO modification of relevant neurogenesis-associated factors. Related Articles | Metrics

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Elucidating the pathological mechanisms of neurodegeneration in the lethal serpinopathy FENIB Elena Miranda, Giovanna Galliciotti 2022, 17 (8):  1733-1734.  doi: 10.4103/1673-5374.332142 Abstract ( 137 )   PDF (408KB) ( 712 )   Save The term serpinopathies was introduced to describe a family of diseases caused by point mutations in serine protease inhibitors, or serpins. Serpins inhibit their cognate protease by an irreversible suicide mechanism starting with the attack of the active site serine on the reactive center loop of the inhibitor, followed by formation of a covalent complex between both proteins, insertion of the reactive center loop of the serpin into its own beta-sheet A, and culminating in distortion of the active site of the serine protease and thus irreversible inactivation. This inhibitory mechanism, reminiscent of the movement of a mousetrap, requires a structural flexibility that proves to be unfavorable when the folding of the serpin is altered by mutations responsible for conformational rearrangements, allowing an intermolecular domain exchange characterized by the insertion of the C-terminal domain of a molecule into a second one, thus forming a dimer. Expansion of this insertion reaction leads to the formation of serpin polymers that accumulate within the endoplasmic reticulum (ER) of the cell and consequently reduces the secretion of the wild-type serpin (Greene et al., 2016). Related Articles | Metrics

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Glial cell line‑derived neurotrophic factor in brain repair after focal ischemic stroke Zhe Zhang, Nannan Zhang, Shinghua Ding 2022, 17 (8):  1735-1736.  doi: 10.4103/1673‑5374.332141 Abstract ( 104 )   PDF (871KB) ( 64 )   Save Cerebral focal ischemic stroke (FIS) is a leading brain disorder associated with human debilitation and death. It is induced by the formation of a thrombus in the arteries that supply blood to the central nervous system. FIS patients may suddenly experience paralysis, impairment of speech and loss of vision. Most patients develop permanent disabilities. In the past decades, enormous efforts have been taken to develop FIS treatment strategies, but unfortunately, there is still a lack of effective ones for this disease. Currently, tissue plasminogen activator is the only Food and Drug Administration approved drug for FIS treatment, however, this method has limited application since it is only effective within 3–5 hours after the onset of FIS. Because of this, the recovery from FIS largely depends on self-brain repair and rehabilitation (Campbell et al., 2019). Related Articles | Metrics

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The second brain in Parkinson’s disease: fact or fantasy? Nehal Yemula, Paul Njoku, Joseph Takyi 2022, 17 (8):  1737-1738.  doi: 10.4103/1673-5374.332144 Abstract ( 139 )   PDF (288KB) ( 102 )   Save Parkinson’s disease (PD) is a movement disorder characterized by reduced dopamine levels due to degeneration of the substantia nigra. The clinical presentation is underlined by bradykinesia, postural instability, and tremors. PD is the second most common neurodegenerative disease worldwide, with a huge monetary burden. In the United States alone, it is estimated that in 2017, the total economic cost was $51.9 billion, and projected to surpass $79 billion by 2037. Extensive research has been conducted into the pathophysiology and clinical implications of the disease. Within neurodegenerative disorder itself, the entity involving the brain-gut axis has been a fundamental model in understanding the disease process. More so than ever in PD, the association between gut health and neurological disease is gaining momentum, with the fascinating idea of influencing neurological health by treating the gut. Related Articles | Metrics

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High mobility group box protein 1 and white matter injury following traumatic brain injury: perspectives on mechanisms and therapeutic strategies Ronak Ved, Susruta Manivannan, Imogen Tasker, Malik Zaben 2022, 17 (8):  1739-1740.  doi: 10.4103/1673-5374.332135 Abstract ( 200 )   PDF (697KB) ( 90 )   Save Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Despite significant medical advances over recent decades, many survivors of TBI develop long term neuro-cognitive deficits. Previously, only moderate and severe injuries were thought to account for the devastating consequences of TBI. However, there is increasing evidence that even milder injuries may result in problematic lifelong cognitive and affective disturbances. TBI is typically characterized by an an acute physical injury followed by a protracted innate neuro-inflammatory response. These reponses, mediated via neuronal, astrocyte and microglial cells, amongst others, and may result in widespread neuronal death and a micro-environment that is not conducive to brain repair (Manivannan et al., 2021). Whilst the primary physical injury often evades intervention from a medical perspective, the subsequent neuro-inflammatory response offers a potential therapeutic target. Nonetheless, effective pharmacological strategies continue to elude clinicians and scientists due to the complex underlying pathogenesis and difficulties of modelling such a heterogeneous disease. However, the majority of research to date has focused on investigating the effects of post-traumatic neuro-inflammation on grey matter injury rather than the consequences upon white matter (WM), which contributes greatly to cognitive dysfunction across many neurological diseases (Filly and Kelly, 2018). Herein, we will briefly discuss: (i) high mobility group box protein 1 (HMGB1) as a potential therapeutic target; (ii) the relevance of WM injury in TBI and current understanding of WM repair following injury; and (iii) perspectives on how HMGB1 may play a role. Related Articles | Metrics

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Recent advancements toward non-invasive imaging of retinal amyloid-beta for early detection of Alzheimer’s disease Liang Wang, Xiaobo Mao 2022, 17 (8):  1741-1742.  doi: 10.4103/1673-5374.332137 Abstract ( 138 )   PDF (1535KB) ( 93 )   Save Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment suggested to be induced by the accumulation of amyloid-β (Aβ) in the brain, especially in the hippocampus. Cerebral Aβ deposits may be detected through positron emission tomography (PET) as early as two decades before clinically diagnosed AD-associated dementia, which provides the opportunity for early therapeutic interventions (Wang and Mao, 2021). PET may not be suitable for AD screening since it is invasive, costly, and inaccessible for routine clinical use or population screening. Aβ deposits have also been identified throughout the retina, which is a developmental outgrowth of the diencephalon and shares physiological and pathological pathways with the central nervous system (London et al., 2013). Patients with mild cognitive impairment and early AD are reported to have visual disturbances involving visual field loss with reported thinning of the retinal layers including the retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer (Koronyo-Hamaoui et al., 2011; Wang and Mao, 2021). Retinal Aβ deposits have been detected prior to the manifestation of cerebral Aβ deposits in transgenic mice models of AD (Koronyo-Hamaoui et al., 2011; Habiba et al., 2021). Since the retina provides an easily accessible location for non-invasive imaging, retinal Aβ may have the potential to be a surrogate for cerebral Aβ and a biomarker for the detection of AD prior to irreversible cognitive impairment. Several techniques have been explored for imaging retinal Aβ, including the use of curcumin and hyperspectral imaging, which have been shown to differentiate AD patients and normal subjects in vivo (Koronyo et al., 2017; Hadoux et al., 2019). These non-invasive, imaging studies have also characterized retinal Aβ in human subjects and found correlations between retinal Aβ and cerebral manifestations including increased cerebral Aβ load and low cognitive assessment scores (Hadoux et al., 2019; Dumitrascu et al., 2020). However, further investigations with larger sample sizes and longitudinal studies are needed to determine if retinal Aβ can be applied in routine clinical settings and potentially for population-based screening. Related Articles | Metrics

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Designing nanocarriers to overcome the limitations in conventional drug administration for Parkinson’s disease Rafael A. García-Muñoz, Joseph McConnell, Victoria Morales, Raul Sanz 2022, 17 (8):  1743-1744.  doi: 10.4103/1673-5374.332143 Abstract ( 161 )   PDF (496KB) ( 85 )   Save Neurodegenerative diseases (NDs) have become one of the leading causes of death and disability worldwide, and cause enormous pain and suffering for both patients and their families. Some of the most common NDs include Alzheimer’s disease, Parkinson’s disease (PD) and Huntington’s disease, among others (Feng, 2020). PD is a widespread neurodegenerative disease that affects more than 10 million people worldwide (No author listed, 2021). The direct cause of the disease is unknown, but it is characterized by the selective degeneration of dopaminergic neurons in the midbrain in the substantia nigra. This leads to the depletion of dopamine (3,4-dihydroxyphenethylamine, DA) in the striatum of patients, in addition to the existence of abnormal α-synuclein in nerve cells and the development of toxic protein aggregates in neurons called Lewy bodies, which causes muscle stiffness, slowness of movements and tremors. It is believed that a combination of genetic and environmental factors may be the cause of PD, but the exact reason for the disease is not yet fully understood. Related Articles | Metrics

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Targeting the epigenome to treat neurodegenerative diseases or delay their onset: a perspective Fabio Coppedè 2022, 17 (8):  1745-1747.  doi: 10.4103/1673-5374.332145 Abstract ( 122 )   PDF (1233KB) ( 82 )   Save Epigenetic mechanisms regulate the chromatin structure and gene expression levels without changing the primary DNA sequence, and include DNA methylation and hydroxymethylation, post-translational modifications of histone tails and nucleosome positioning, as well as mechanisms mediated by long and short non-coding RNA molecules. These mechanisms are required for human development and cell differentiation, and are pivotal in differentiated cells for cellular functions, allowing a tight regulation of gene expression levels in response to environmental stimuli and cellular metabolic demands (Coppedè, 2021b). Particularly, the neuronal epigenome is highly sensitive to external stimuli and its function is required for learning and memory processes (Creighton et al., 2020). Several enzymes, collectively referred to as the “epigenetic machinery”, add, remove and read epigenetic marks, allowing chromatin remodeling to promote or repress gene transcription. The activity of these enzymes allows the reversibility of epigenetic marks, which is pivotal in neurons for memory formation and consolidation (Creighton et al., 2020). The epigenome is altered in the aging brain, although the factors driving these changes, their contribution to age-related memory decline, and their potential modulation with environmental interventions are still a matter of debate (Creighton et al., 2020). Furthermore, both global and gene-specific epigenetic changes are observed in blood and brain tissues of individuals with major neurodegenerative diseases, including among others Alzheimer’s disease (AD) (Coppedè, 2021a), Parkinson’s disease (PD) (Rathore et al., 2020), and amyotrophic lateral sclerosis (ALS) (Coppedè, 2020). An open question is which of these changes result from gene-environment interactions that lead to age-related declines in cognitive and motor functions, thus contributing to the onset of the disease, and which ones are consequences of the degenerative processes occurring in neurons. However, due to their reversibility, several epigenetic marks have been proposed as potential therapeutic targets to treat or delay neurodegeneration (Coppedè, 2021a). In the present article, the author provides a brief overview of the literature and its own perspective opinion on targeting the epigenome to treat neurodegeneration. Related Articles | Metrics

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Flow cytometry and stroke: from current methodology to future applications Sylvie Amu, Kyle Malone 2022, 17 (8):  1748-1750.  doi: 10.4103/1673-5374.332138 Abstract ( 161 )   PDF (891KB) ( 102 )   Save Flow cytometry is a versatile technique for analyzing stroke-induced changes in the immune system. Unlike other methods of cell identification such as immunohistochemistry, the technique is rapid, highly sensitive, and capable of quantifying multiple markers in cell suspensions. Utilizing cell sorters, flow cytometers can also produce highly enriched populations of viable cells for functional studies. The aim of this perspective is to appraise current flow cytometry methods in the field of stroke, provide guidance on best practices, and outline some of the future applications of the technique in pre-clinical and clinical stroke research. Related Articles | Metrics

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A novel approach in preventing vascular leakage and angiogenesis in wet age-related macular degeneration Kaori H. Yamada 2022, 17 (8):  1751-1752.  doi: 10.4103/1673-5374.332147 Abstract ( 169 )   PDF (870KB) ( 127 )   Save The vascular system carries blood throughout the body to supply oxygen and nutrients to tissues and remove waste from tissues. Dysfunction of the vascular system worsens many diseases. In this perspective, vascular function in blinding eye diseases, current therapies, and our developing approach will be introduced. Related Articles | Metrics

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Evaluation of suprachiasmatic nucleus in Alzheimer’s disease with non-invasive magnetic resonance methods Rico Singer, A. Alia 2022, 17 (8):  1753-1754.  doi: 10.4103/1673-5374.332136 Abstract ( 143 )   PDF (410KB) ( 40 )   Save AD is the most frequently diagnosed form of dementia, with the total number of AD patients worldwide expected to triple by 2050 compared to 2015 (Prince et al., 2015). Despite years of research, much of the AD pathology remains unclear with no treatment or cure available. Besides its two hallmarks, amyloid-β (Aβ) plagues and hyperphosphorylated tau tangles, a distortion of circadian rhythms is commonly observed. Furthermore, poor sleep quality or trouble falling asleep are common AD symptoms, sometimes developing 10–15 years before cognitive symptoms associated with AD (Ju et al., 2014). Related Articles | Metrics

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Ocular therapies for neuronal ceroid lipofuscinoses: more than meets the eye Samantha J. Murray, Nadia L. Mitchell 2022, 17 (8):  1755-1756.  doi: 10.4103/1673-5374.332148 Abstract ( 154 )   PDF (285KB) ( 58 )   Save The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of inherited, neurodegenerative, lysosomal storage diseases typically manifesting in childhood. There are currently 13 known forms of NCL resulting from various mutations in the CLN (ceroid lipofuscinoses neuronal) genes (CLN1-8 and CLN10-14). Although varying in onset and severity, the NCLs share several phenotypic features including seizures, motor dysfunction, cognitive decline, and progressive loss of vision (Mole et al., 2011). Current treatment strategies being investigated in pre-clinical studies and early stage clinical trials primarily target the brain and spinal cord. While these potential therapeutics show promise in attenuating neurological disease, protection against retinal dysfunction and degeneration is generally ineffective or not reported. Related Articles | Metrics

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How mind-body therapies might reduce pathological features of Alzheimer’s disease Melanie Hüttenrauch, Susana Castro-Obregón 2022, 17 (8):  1757-1758.  doi: 10.4103/1673-5374.332146 Abstract ( 144 )   PDF (342KB) ( 110 )   Save Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder that is responsible for around 60–80% of all dementia cases and currently affects around 50 million people worldwide. As the population’s life span tends to increase, current predictions suggest that by 2050, 152 million people worldwide will suffer from dementia (Balsinha, 2019). While the exact cause of AD remains obscure, various hypotheses regarding AD etiology have been described in the last decades. According to the amyloid hypothesis, the pathogenic changes related to AD start with the accumulation of amyloid-beta (Aβ) in the brain. These Aβ peptides form oligomers and insoluble amyloid plaques which are neurotoxic and trigger harmful downstream events such as the aggregation of the microtubule-associated protein Tau into neurofibrillary tangles, chronic inflammation, and brain atrophy. Related Articles | Metrics

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Melatonin, circadian rhythms and glaucoma: current perspective Denis Gubin, Dietmar Weinert 2022, 17 (8):  1759-1760.  doi: 10.4103/1673-5374.332149 Abstract ( 304 )   PDF (355KB) ( 194 )   Save Living by the clock, in alignment with external time cues is an important condition for human health and well-being. Periodic changes in the ambient light serve as a key factor to synchronize the endogenously generated circadian rhythms. The retina perceives the photic signals and transmits them to the central body clock, the suprachiasmatic nuclei (SCN), via the retinohypothalamic tract. Related Articles | Metrics

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Do pyroptosis, apoptosis, and necroptosis (PANoptosis) exist in cerebral ischemia? Evidence from cell and rodent studies Wei-Tao Yan, Yan-Di Yang, Xi-Min Hu, Wen-Ya Ning, Lyu-Shuang Liao, Shuang Lu, Wen-Juan Zhao, Qi Zhang, Kun Xiong 2022, 17 (8):  1761-1768.  doi: 10.4103/1673-5374.331539 Abstract ( 328 )   PDF (1180KB) ( 294 )   Save Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis, apoptosis and necroptosis act in consort in a multimeric protein complex, PANoptosome. This allows all the components of PANoptosis to be regulated simultaneously. PANoptosis provides a new way to study the regulation of cell death, in that different types of cell death may be regulated at the same time. To test whether PANoptosis exists in diseases other than infectious diseases, we chose cerebral ischemia/reperfusion injury as the research model, collected articles researching cerebral ischemia/reperfusion from three major databases, obtained the original research data from these articles by bibliometrics, data mining and other methods, then integrated and analyzed these data. We selected papers that investigated at least two of the components of PANoptosis to check its occurrence in ischemia/reperfusion. In the cell model simulating ischemic brain injury, pyroptosis, apoptosis and necroptosis occur together and this phenomenon exists widely in different passage cell lines or primary neurons. Pyroptosis, apoptosis and necroptosis also occurred in rat and mouse models of ischemia/reperfusion injury. This confirms that PANoptosis is observed in ischemic brain injury and indicates that PANoptosis can be a target in the regulation of various central nervous system diseases. Related Articles | Metrics

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microRNA-455-5p alleviates neuroinflammation in cerebral ischemia/reperfusion injury Jian-Song Zhang, Pin-Pin Hou, Shuai Shao, Anatol Manaenko, Zhi-Peng Xiao, Yan Chen, Bing Zhao, Feng Jia, Xiao-Hua Zhang, Qi-Yong Mei, Qin Hu 2022, 17 (8):  1769-1775.  doi: 10.4103/1673-5374.332154 Abstract ( 239 )   PDF (2493KB) ( 175 )   Save Neuroinflammation is a major pathophysiological factor that results in the development of brain injury after cerebral ischemia/reperfusion. Downregulation of microRNA (miR)-455-5p after ischemic stroke has been considered a potential biomarker and therapeutic target for neuronal injury after ischemia. However, the role of miR-455-5p in the post-ischemia/reperfusion inflammatory response and the underlying mechanism have not been evaluated. In this study, mouse models of cerebral ischemia/reperfusion injury were established by transient occlusion of the middle cerebral artery for 1 hour followed by reperfusion. Agomir-455-5p, antagomir-455-5p, and their negative controls were injected intracerebroventricularly 2 hours before or 0 and 1 hour after middle cerebral artery occlusion (MCAO). The results showed that cerebral ischemia/reperfusion decreased miR-455-5p expression in the brain tissue and the peripheral blood. Agomir-455-5p pretreatment increased miR-455-5p expression in the brain tissue, reduced the cerebral infarct volume, and improved neurological function. Furthermore, primary cultured microglia were exposed to oxygen-glucose deprivation for 3 hours followed by 21 hours of reoxygenation to mimic cerebral ischemia/reperfusion. miR-455-5p reduced C-C chemokine receptor type 5 mRNA and protein levels, inhibited microglia activation, and reduced the production of the inflammatory factors tumor necrosis factor-α and interleukin-1β. These results suggest that miR-455-5p is a potential biomarker and therapeutic target for the treatment of cerebral ischemia/reperfusion injury and that it alleviates cerebral ischemia/reperfusion injury by inhibiting C-C chemokine receptor type 5 expression and reducing the neuroinflammatory response. Related Articles | Metrics

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Essential role of MALAT1 in reducing traumatic brain injury Na Wu, Chong-Jie Cheng, Jian-Jun Zhong, Jun-Chi He, Zhao-Si Zhang, Zhi-Gang Wang, Xiao-Chuan Sun, Han Liu 2022, 17 (8):  1776-1784.  doi: 10.4103/1673-5374.332156 Abstract ( 171 )   PDF (12943KB) ( 18 )   Save As a highly evolutionary conserved long non-coding RNA, metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was first demonstrated to be related to lung tumor metastasis by promoting angiogenesis. To investigate the role of MALAT1 in traumatic brain injury, we established mouse models of controlled cortical impact and cell models of oxygen-glucose deprivation to mimic traumatic brain injury in vitro and in vivo. The results revealed that MALAT1 silencing in vitro inhibited endothelial cell viability and tube formation but increased migration. In MALAT1-deficient mice, endothelial cell proliferation in the injured cortex, functional vessel density and cerebral blood flow were reduced. Bioinformatic analyses and RNA pull-down assays validated enhancer of zeste homolog 2 (EZH2) as a downstream factor of MALAT1 in endothelial cells. Jagged-1, the Notch homolog 1 (NOTCH1) agonist, reversed the MALAT1 deficiency-mediated impairment of angiogenesis. Taken together, our results suggest that MALAT1 controls the key processes of angiogenesis following traumatic brain injury in an EZH2/NOTCH1-dependent manner. Related Articles | Metrics

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Dose optimization of intrathecal administration of human umbilical cord mesenchymal stem cells for the treatment of subacute incomplete spinal cord injury Ting-Ting Cao, Huan Chen, Mao Pang, Si-Si Xu, Hui-Quan Wen, Bin Liu, Li-Min Rong, Mang-Mang Li 2022, 17 (8):  1785-1794.  doi: 10.4103/1673-5374.332151 Abstract ( 210 )   PDF (4567KB) ( 133 )   Save Human umbilical cord mesenchymal stem cells (hUC-MSCs) are a promising candidate for spinal cord injury (SCI) repair owing to their advantages of low immunogenicity and easy accessibility over other MSC sources. However, modest clinical efficacy hampered the progression of these cells to clinical translation. This discrepancy may be due to many variables, such as cell source, timing of implantation, route of administration, and relevant efficacious cell dose, which are critical factors that affect the efficacy of treatment of patients with SCI. Previously, we have evaluated the safety and efficacy of 4 × 106 hUC-MSCs/kg in the treatment of subacute SCI by intrathecal implantation in rat models. To search for a more accurate dose range for clinical translation, we compared the effects of three different doses of hUC-MSCs – low (0.25 × 106 cells/kg), medium (1 × 106 cells/kg) and high (4 × 106 cells/kg) – on subacute SCI repair through an elaborate combination of behavioral analyses, anatomical analyses, magnetic resonance imaging-diffusion tensor imaging (MRI-DTI), biotinylated dextran amine (BDA) tracing, electrophysiology, and quantification of mRNA levels of ion channels and neurotransmitter receptors. Our study demonstrated that the medium dose, but not the low dose, is as efficient as the high dose in producing the desired therapeutic outcomes. Furthermore, partial restoration of the γ-aminobutyric acid type A (GABAA) receptor expression by the effective doses indicates that GABAA receptors are possible candidates for therapeutic targeting of dormant relay pathways in injured spinal cord. Overall, this study revealed that intrathecal implantation of 1 × 106 hUC-MSCs/kg is an alternative approach for treating subacute SCI. Related Articles | Metrics

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Oxidized low-density lipoprotein receptor 1: a novel potential therapeutic target for intracerebral hemorrhage Hui-Yuan Zhang, Xi Lu, Yue-Han Hao, Ling Tang, Zhi-Yi He 2022, 17 (8):  1795-1801.  doi: 10.4103/1673-5374.332157 Abstract ( 189 )   PDF (3218KB) ( 127 )   Save Oxidized low-density lipoprotein receptor 1 (OLR1) is upregulated in neurons and participates in hypertension-induced neuronal apoptosis. OLR1 deletion exerts protective effects on cerebral damage induced by hypertensive-induced stroke. Therefore, OLR1 is likely involved in the progress of intracerebral hemorrhage. In this study, we examined the potential role of OLR1 in intracerebral hemorrhage using a rat model. OLR1 small interfering RNA (10 μL; 50 pmol/μL) was injected into the right basal ganglia to knock down OLR1. Twenty-four hours later, 0.5 U collagenase type VII was injected to induce intracerebral hemorrhage. We found that knockdown of OLR1 attenuated neurological behavior impairment in rats with intracerebral hemorrhage and reduced hematoma, neuron loss, inflammatory reaction, and oxidative stress in rat brain tissue. We also found that silencing of OLR1 suppressed ferroptosis induced by intracerebral hemorrhage and the p38 signaling pathway. Therefore, silencing OLR1 exhibits protective effects against secondary injury of intracerebral hemorrhage. These findings suggest that OLR1 may be a novel potential therapeutic target for intracerebral hemorrhage. Related Articles | Metrics

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Mice lacking perforin have improved regeneration of the injured femoral nerve Igor Jakovčevski, Monika von Düring, David Lutz, Maja Vulović, Mohammad Hamad, Gebhard Reiss, Eckart Förster, Melitta Schachner 2022, 17 (8):  1802-1808.  doi: 10.4103/1673-5374.332152 Abstract ( 162 )   PDF (4695KB) ( 110 )   Save The role that the immune system plays after injury of the peripheral nervous system is still not completely understood. Perforin, a natural killer cell- and T-lymphocyte-derived enzyme that mediates cytotoxicity, plays important roles in autoimmune diseases, infections and central nervous system trauma, such as spinal cord injury. To dissect the roles of this single component of the immune response to injury, we tested regeneration after femoral nerve injury in perforin-deficient (Pfp–/–) and wild-type control mice. Single frame motion analysis showed better motor recovery in Pfp–/– mice compared with control mice at 4 and 8 weeks after injury. Retrograde tracing of the motoneuron axons regrown into the motor nerve branch demonstrated more correctly projecting motoneurons in the spinal cord of Pfp–/– mice compared with wild-types. Myelination of regrown axons measured by g-ratio was more extensive in Pfp–/– than in wild-type mice in the motor branch of the femoral nerve. Pfp–/– mice displayed more cholinergic synaptic terminals around cell bodies of spinal motoneurons after injury than the injured wild-types. We histologically analyzed lymphocyte infiltration 10 days after surgery and found that in Pfp–/– mice the number of lymphocytes in the regenerating nerves was lower than in wild-types, suggesting a closed blood-nerve barrier in Pfp–/– mice. We conclude that perforin restricts motor recovery after femoral nerve injury owing to decreased survival of motoneurons and reduced myelination. Related Articles | Metrics

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Efficacy and safety of transcutaneous auricular vagus nerve stimulation combined with conventional rehabilitation training in acute stroke patients: a randomized controlled trial conducted for 1 year involving 60 patients Jia-Ni Li, Chen-Chen Xie, Chang-Qing Li, Gui-Fang Zhang, Hao Tang, Chuan-Na Jin, Jing-Xi Ma, Lan Wen, Ke-Ming Zhang, Ling-Chuan Niu 2022, 17 (8):  1809-1813.  doi: 10.4103/1673-5374.332155 Abstract ( 304 )   PDF (690KB) ( 718 )   Save Transcutaneous auricular vagus nerve stimulation (ta-VNS) is a novel noninvasive treat-ment for stroke that directly stimulates the peripheral auricular branch of the vagus nerve. There have been recent reports that ta-VNS combined with conventional rehabilitation training promotes the recovery of neurological function of patients with acute stroke. However, these were small-sample-sized studies on the recovery of neurological function in patients after percutaneous vagus nerve stimulation in the subacute and chronic phases after stroke. This double-blinded randomized controlled trial involved 60 acute ischemic or hemorrhagic stroke patients aged 18–80 years who received treatment in the Second Affiliated Hospital of Chongqing Medical University. The subjects were randomly assigned to receive ta-VNS or sham ta-VNS combined with conventional rehabilitation training. The follow-up results over 1 year revealed that ta-VNS combined with conventional rehabilitation training greatly improved the recovery of motor and sensory functions and emotional responses compared with sham ta-VNS combined with conventional rehabilitation training. There were no obvious side effects. These findings suggest that ta-VNS combined with conventional rehabilitation training for the treatment of acute ischemic or hemorrhagic stroke patients is safe and effective. Related Articles | Metrics

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Reducing host aldose reductase activity promotes neuronal differentiation of transplanted neural stem cells at spinal cord injury sites and facilitates locomotion recovery Kun Zhang, Wen-Can Lu, Ming Zhang, Qian Zhang, Pan-Pan Xian, Fang-Fang Liu, Zhi-Yang Chen, Chung Sookja Kim, Sheng-Xi Wu, Hui-Ren Tao, Ya-Zhou Wang 2022, 17 (8):  1814-1820.  doi: 10.4103/1673-5374.330624 Abstract ( 152 )   PDF (9127KB) ( 36 )   Save Neural stem cell (NSC) transplantation is a promising strategy for replacing lost neurons following spinal cord injury. However, the survival and differentiation of transplanted NSCs is limited, possibly owing to the neurotoxic inflammatory microenvironment. Because of the important role of glucose metabolism in M1/M2 polarization of microglia/macrophages, we hypothesized that altering the phenotype of microglia/macrophages by regulating the activity of aldose reductase (AR), a key enzyme in the polyol pathway of glucose metabolism, would provide a more beneficial microenvironment for NSC survival and differentiation. Here, we reveal that inhibition of host AR promoted the polarization of microglia/macrophages toward the M2 phenotype in lesioned spinal cord injuries. M2 macrophages promoted the differentiation of NSCs into neurons in vitro. Transplantation of NSCs into injured spinal cords either deficient in AR or treated with the AR inhibitor sorbinil promoted the survival and neuronal differentiation of NSCs at the injured spinal cord site and contributed to locomotor functional recovery. Our findings suggest that inhibition of host AR activity is beneficial in enhancing the survival and neuronal differentiation of transplanted NSCs and shows potential as a treatment of spinal cord injury. Related Articles | Metrics

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Effects of cortical intermittent theta burst stimulation combined with precise root stimulation on motor function after spinal cord injury: a case series study Ye-Ran Mao, Zhong-Xia Jin, Ya Zheng, Jian Fan, Li-Juan Zhao, Wei Xu, Xiao Hu, Chun-Ya Gu, Wei-Wei Lu, Guang-Yue Zhu, Yu-Hui Chen, Li-Ming Cheng, Dong-Sheng Xu 2022, 17 (8):  1821-1826.  doi: 10.4103/1673-5374.332158 Abstract ( 172 )   PDF (710KB) ( 146 )   Save Activation and reconstruction of the spinal cord circuitry is important for improving motor function following spinal cord injury. We conducted a case series study to investigate motor function improvement in 14 patients with chronic spinal cord injury treated with 4 weeks of unilateral (right only) cortical intermittent theta burst stimulation combined with bilateral magnetic stimulation of L3–L4 nerve roots, five times a week. Bilateral resting motor evoked potential amplitude was increased, central motor conduction time on the side receiving cortical stimulation was significantly decreased, and lower extremity motor score, Berg balance score, spinal cord independence measure-III score, and 10 m-walking speed were all increased after treatment. Right resting motor evoked potential amplitude was positively correlated with lower extremity motor score after 4 weeks of treatment. These findings suggest that cortical intermittent theta burst stimulation combined with precise root stimulation can improve nerve conduction of the corticospinal tract and lower limb motor function recovery in patients with chronic spinal cord injury. Related Articles | Metrics

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Effects of targeted muscle reinnervation on spinal cord motor neurons in rats following tibial nerve transection Wei Lu, Jian-Ping Li, Zhen-Dong Jiang, Lin Yang, Xue-Zheng Liu 2022, 17 (8):  1827-1832.  doi: 10.4103/1673-5374.332153 Abstract ( 145 )   PDF (40985KB) ( 53 )   Save Targeted muscle reinnervation (TMR) is a surgical procedure used to transfer residual peripheral nerves from amputated limbs to targeted muscles, which allows the target muscles to become sources of motor control information for function reconstruction. However, the effect of TMR on injured motor neurons is still unclear. In this study, we aimed to explore the effect of hind limb TMR surgery on injured motor neurons in the spinal cord of rats after tibial nerve transection. We found that the reduction in hind limb motor function and atrophy in mice caused by tibial nerve transection improved after TMR. TMR enhanced nerve regeneration by increasing the number of axons and myelin sheath thickness in the tibial nerve, increasing the number of anterior horn motor neurons, and increasing the number of choline acetyltransferase-positive cells and immunofluorescence intensity of synaptophysin in rat spinal cord. Our findings suggest that TMR may enable the reconnection of residual nerve fibers to target muscles, thus restoring hind limb motor function on the injured side. Related Articles | Metrics

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Peripheral nerve fibroblasts secrete neurotrophic factors to promote axon growth of motoneurons Qian-Ru He, Meng Cong, Fan-Hui Yu, Yu-Hua Ji, Shu Yu, Hai-Yan Shi, Fei Ding 2022, 17 (8):  1833-1840.  doi: 10.4103/1673-5374.332159 Abstract ( 392 )   PDF (14802KB) ( 120 )   Save Peripheral nerve fibroblasts play a critical role in nerve development and regeneration. Our previous study found that peripheral nerve fibroblasts have different sensory and motor phenotypes. Fibroblasts of different phenotypes can guide the migration of Schwann cells to the same sensory or motor phenotype. In this study, we analyzed the different effects of peripheral nerve-derived fibroblasts and cardiac fibroblasts on motoneurons. Compared with cardiac fibroblasts, peripheral nerve fibroblasts greatly promoted motoneuron neurite outgrowth. Transcriptome analysis results identified 491 genes that were differentially expressed in peripheral nerve fibroblasts and cardiac fibroblasts. Among these, 130 were significantly upregulated in peripheral nerve fibroblasts compared with cardiac fibroblasts. These genes may be involved in axon guidance and neuron projection. Three days after sciatic nerve transection in rats, peripheral nerve fibroblasts accumulated in the proximal and distal nerve stumps, and most expressed brain-derived neurotrophic factor. In vitro, brain-derived neurotrophic factor secreted from peripheral nerve fibroblasts increased the expression of β-actin and F-actin through the extracellular regulated protein kinase and serine/threonine kinase pathways, and enhanced motoneuron neurite outgrowth. These findings suggest that peripheral nerve fibroblasts and cardiac fibroblasts exhibit different patterns of gene expression. Peripheral nerve fibroblasts can promote motoneuron neurite outgrowth. Related Articles | Metrics

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Crry silencing alleviates Alzheimer’s disease injury by regulating neuroinflammatory cytokines and the complement system Xi-Chen Zhu, Lu Liu, Wen-Zhuo Dai, Tao Ma 2022, 17 (8):  1841-1849.  doi: 10.4103/1673-5374.332160 Abstract ( 238 )   PDF (3934KB) ( 137 )   Save Complement component (3b/4b) receptor 1 (CR1) expression is positively related to the abundance of phosphorylated microtubule-associated protein tau (tau), and CR1 expression is associated with susceptibility to Alzheimer’s disease. However, the exact role of CR1 in tau protein-associated neurodegenerative diseases is unknown. In this study, we show that the mouse Cr1-related protein Y (Crry) gene, Crry, is localized to microglia. We also found that Crry protein expression in the hippocampus and cortex was significantly elevated in P301S mice (a mouse model widely used for investigating tau pathology) compared with that in wild-type mice. Tau protein phosphorylation (at serine 202, threonine 205, threonine 231, and serine 262) and expression of the major tau kinases glycogen synthase kinase-3 beta and cyclin-dependent-like kinase 5 were greater in P301S mice than in wild-type mice. Crry silencing by lentivirus-transfected short hairpin RNA led to greatly reduced tau phosphorylation and glycogen synthase kinase-3 beta and cyclin-dependent-like kinase 5 activity. Crry silencing reduced neuronal apoptosis and rescued cognitive impairment of P301S mice. Crry silencing also reduced the levels of the neuroinflammatory factors interleukin-1 beta, tumor necrosis factor alpha, and interleukin-6 and the complement components complement 3 and complement component 3b. Our results suggest that Crry silencing in the P301S mouse model reduces tau protein phosphorylation by reducing the levels of neuroinflammation and complement components, thereby improving cognitive function. Related Articles | Metrics

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Acupuncture enhances brain function in patients with mild cognitive impairment: evidence from a functional-near infrared spectroscopy study M. N. Afzal Khan, Usman Ghafoor, Ho-Ryong Yoo, Keum-Shik Hong 2022, 17 (8):  1850-1856.  doi: 10.4103/1673-5374.332150 Abstract ( 239 )   PDF (7839KB) ( 125 )   Save Mild cognitive impairment (MCI) is a precursor to Alzheimer’s disease. It is imperative to develop a proper treatment for this neurological disease in the aging society. This observational study investigated the effects of acupuncture therapy on MCI patients. Eleven healthy individuals and eleven MCI patients were recruited for this study. Oxy- and deoxy-hemoglobin signals in the prefrontal cortex during working-memory tasks were monitored using functional near-infrared spectroscopy. Before acupuncture treatment, working-memory experiments were conducted for healthy control (HC) and MCI groups (MCI-0), followed by 24 sessions of acupuncture for the MCI group. The acupuncture sessions were initially carried out for 6 weeks (two sessions per week), after which experiments were performed again on the MCI group (MCI-1). This was followed by another set of acupuncture sessions that also lasted for 6 weeks, after which the experiments were repeated on the MCI group (MCI-2). Statistical analyses of the signals and classifications based on activation maps as well as temporal features were performed. The highest classification accuracies obtained using binary connectivity maps were 85.7% HC vs. MCI-0, 69.5% HC vs. MCI-1, and 61.69% HC vs. MCI-2. The classification accuracies using the temporal features mean from 5 seconds to 28 seconds and maximum (i.e, max(5:28 seconds)) values were 60.6% HC vs. MCI-0, 56.9% HC vs. MCI-1, and 56.4% HC vs. MCI-2. The results reveal that there was a change in the temporal characteristics of the hemodynamic response of MCI patients due to acupuncture. This was reflected by a reduction in the classification accuracy after the therapy, indicating that the patients’ brain responses improved and became comparable to those of healthy subjects. A similar trend was reflected in the classification using the image feature. These results indicate that acupuncture can be used for the treatment of MCI patients. Related Articles | Metrics