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15 June 2024, Volume 19 Issue 6 Previous Issue   

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Neurovascular unit on a chip: the relevance and maturity as an advanced in vitro model Sujey Palma-Florez, Anna Lagunas, Mònica Mir 2024, 19 (6):  1165-1166.  doi: 10.4103/1673-5374.385863 Abstract ( 106 )   PDF (1232KB) ( 93 )   Save The brain is a high-energy demanding organ, consuming around 20% of the metabolic energy generated. To fulfill this demand, cerebral blood flow (CBF) supplies oxygen and glucose continuously through the intricate network of cerebral blood vessels. Although for many years brain activity and blood flow were conceived as independent processes, MRI-based functional brain imaging demonstrated that there is a coupling between them, leading to the concept of the neurovascular unit (NVU) to reflect their interplay (Raichle and Mintun, 2006). The cerebrovascular system is far from being homogeneous throughout its structure; rather, each specific region of the brain presents multiple architectures. The NVU structure is divided into three main regions: cerebral arteries, including the middle cerebral artery. Middle cerebral artery gives rise to a second region, the pial arteries from the surface of the brain within the subarachnoid space. The endothelial cells (ECs) of pial arteries are covered by smooth muscle cells (SMCs) and are separated by a collagenous elastic lamina. From pial arteries, a subset of arterioles penetrates deep into the brain (penetrating arterioles) through the perivascular space, which limits glial cells. The perivascular space allocates several cell types; perivascular macrophages, mato, pial and mast cells. In this region, most external penetrating arterioles preserve a thin layer of SMCs and innervation. As arterioles get deeper into the brain, they become thinner, glial membrane and vascular basement membrane fuse occluding the perivascular space, innervation and SMCs disappear, which is ultimately substituted by pericytes in the microvascular capillaries, going to a less contractile vascularization. The collagen-rich matrix of pial arteries and brain capillaries are more abundant in proteoglycans and regulatory factors.  Related Articles | Metrics

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Does astrocytic L-lactate enhance cognition through myelination? Mastura Akter, Ying Li 2024, 19 (6):  1167-1168.  doi: 10.4103/1673-5374.385872 Abstract ( 109 )   PDF (492KB) ( 73 )   Save Introduction: Astrocytes, the predominant glial cell in the brain, play a vital role in a plethora of central nervous system functions. They are the major storage site of glycogen in the central nervous system. They produce L-lactate by glycogenolysis and glycolysis which is then transported to neurons (Magistretti and Allaman, 2018). Multiple evidence using diverse behavioral paradigms, such as fear conditioning, conditioned place avoidance, rat gambling task (RGT), and flavor-place paired associate (PA) learning suggest that L-lactate has a beneficial effect on various aspects of cognition (Wang et al., 2017; Akter et al., 2023b). While the molecular mechanisms underlying the cognitive benefits of L-lactate are still emerging, it is well-established that astrocytic L-lactate can be used as an energy substrate by neurons and can induce N-methyl-D-aspartate receptor-dependent plasticity-driven gene expression during cognition (Magistretti and Allaman, 2018). Additionally, recent evidence has revealed more roles of L-lactate which include myelination, neuronal mitochondrial biogenesis, and antioxidant defense (Sanchez-Abarca et al., 2001; Ichihara et al., 2017; Akter et al., 2023a, b). Myelin in the central nervous system is a specialized lipid-rich membrane formed by oligodendrocytes. It ensheathes axons and facilitates the fast and synchronized transfer of information between neurons. Multiple studies, as reviewed by (Xin and Chan, 2020), have suggested that oligodendrocytes and myelin play an important role in modulating cognitive functions such as motor learning, spatial learning, and fear learning. By synthesizing recent evidence, this perspective posits that astrocytic L-lactate-mediated cognitive enhancement, particularly schema memory and decision-making, may be mediated by myelination facilitated by L-lactate. Related Articles | Metrics

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CRABP1-mediated non-canonical retinoic acid signaling in motor neurons and neural stem cells Li-Na Wei 2024, 19 (6):  1169-1170.  doi: 10.4103/1673-5374.385866 Abstract ( 126 )   PDF (436KB) ( 19 )   Save Retinoic acid (RA), the active metabolite of vitamin A (the retinoids), elicits a wide spectrum of biological activities critical to the development and health of most of the organ systems including the nervous systems (Corcoran et al., 2002). The effects of RA are mediated by two very distinct pathways; the first is manifested in the nucleus by binding to a large family of nuclear RA receptors (RARs) to regulate proper expression of RA-targeted genes, and the second occurs in the cytoplasm by binding to a specific cytoplasmic protein named cellular RA binding protein 1 (CRABP1) to modulate specific cytosolic signaling (Nhieu et al., 2022). The RAR-mediated gene-regulatory activity is referred to as “canonical” and is important for many cellular processes such as cell lineage determination, maintenance, differentiation, function, and survival. The CRABP1-mediated activity of RA is referred to as “non-canonical”, characterized by its rapid, transient, and modulatory feature (Nhieu et al., 2022). While this CRABP1-mediated non-canonical activity of RA was established only recently, it has been increasingly supported by accumulated evidence in recent studies of Crabp1 knockout (CKO) mice.  Related Articles | Metrics

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Building the toolbox for in vivo glia-to-neuron reprogramming Ye Xie, Bo Chen 2024, 19 (6):  1171-1172.  doi: 10.4103/1673-5374.385869 Abstract ( 99 )   PDF (833KB) ( 31 )   Save Unlike regenerative-competent species that possess a remarkable intrinsic capacity to replenish lost neurons and restore neurocircuits spontaneously, the central nervous system in adult mammals lacks the ability to compensate for the neuronal loss caused by neurodegenerative diseases or traumatic injuries resulting in permanent loss of functionality. Inspired by earlier discoveries that radial glia or astrocytes isolated from the postnatal cortex can generate neurons, and fully differentiated somatic cells can be “reprogrammed” back to a pluripotent state driven by defined transcription factors, regenerative strategies to reprogram resident glial cells, such as astrocytes, Müller glia (MG), NG2-glia, and microglia, into neurons in vivo has emerged during the past decade. Theoretically, terminally differentiated cells could be converted from one fate to another using this strategy, especially when cells are lineage-related or originated from a common ancestor.  Related Articles | Metrics

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The immune system: uncharted pathways between senses and the brain Noelia Casares, Mar Cuadrado-Tejedor, Ana García-Osta, Juan José Lasarte 2024, 19 (6):  1173-1174.  doi: 10.4103/1673-5374.385874 Abstract ( 106 )   PDF (2878KB) ( 36 )   Save Humans and animals use the classic five senses -sight, hearing, touch, smell, and taste- to detect and monitor their environment, with the sense of position and movement often referred to as the sixth sense. The perception of external signals through the senses is essential to an organism’s survival, transmitting signals to the central nervous system (CNS) and prompting physiological changes in other biological systems. In addition to the direct effects of sense-induced mediators in the brain, the perception of external signals can significantly affect the immune system that in turn can also affect the CNS and cognition.  Related Articles | Metrics

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Dual PPAR delta/gamma agonists offer therapeutic potential for Alzheimer’s disease Ian Steinke, Meenakshi Singh, Rajesh Amin 2024, 19 (6):  1175-1176.  doi: 10.4103/1673-5374.386410 Abstract ( 109 )   PDF (3614KB) ( 75 )   Save The increasing incidence of Alzheimer’s disease (AD) in the aging population, indicates the critical need for the development of novel targeted molecular therapies for ameliorating AD pathology. Moreover, clinical and pre-clinical evidence demonstrates that peroxisomal proliferator activating receptors (PPAR) agonists regulate energy and lipid homeostasis in models of diabetes, as well as improve spatial memory in animal models of AD (Khan et al., 2019). Mechanistically, PPARs are nuclear transcription factors that form heterodimeric complexes with retinoid X receptors. PPARs are key mediators responsible for the activation of genes involved in cell metabolism, differentiation, and development. More specifically they regulate the transcription of genes associated with energy homeostasis e.g., glucose metabolism, lipid transport, insulin sensitivity, mitochondrial biogenesis, and thermogenesis. They exists in three highly conserved isoforms, gamma (γ), delta (δ/β), and alpha (α). These highly conserved isoforms are well known for their clinical importance for example; PPARα agonists include the fibrates class of drugs (hypercholesterolemia) and PPARα consist of the thiazolidinedione class of drugs for type 2 diabetes (Zhang et al., 2020). Considering these findings, extensive investigation on PPAR agonists, showed reduced levels of amyloid plaques and tau hyperphosphorylation i.e., pathological hallmarks of AD via exhibiting anti-inflammatory properties, regulating ATP metabolism by reducing oxidative stress in mitochondria and improving symptoms associated with behavioral deficits and cognitive decline (Zhen et al., 2023).  Related Articles | Metrics

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Anoctamin 4 defines glucose-inhibited neurons in the ventromedial hypothalamus Longlong Tu, Yanlin He, Yong Xu 2024, 19 (6):  1177-1178.  doi: 10.4103/1673-5374.385867 Abstract ( 102 )   PDF (537KB) ( 35 )   Save Glucose is the primary fuel source of the brain, and therefore glucose levels need to be tightly regulated and maintained within a small physiological range. Certainly, the body necessitates a stable supply of energy mainly provided by glucose for various bodily functions. High or low blood glucose levels would impair the physiological functions of various organs of the body. Prolonged high blood glucose (i.e., hyperglycemia) would cause damage to the blood vessels, nerves, and other organs (e.g., heart, kidneys, and eyes). Low blood glucose (i.e., hypoglycemia) would undermine brain functions and lead to seizures, loss of consciousness, and other serious complications including death. Related Articles | Metrics

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Imaging mass spectrometry: a molecular microscope for studying the role of lipids in Parkinson’s disease Vinata Vedam-Mai, Jacob M. Samuel, Boone M. Prentice 2024, 19 (6):  1179-1180.  doi: 10.4103/1673-5374.385862 Abstract ( 79 )   PDF (826KB) ( 38 )   Save Parkinson’s disease–A lipidopathy? The histopathological hallmark of Parkinson’s disease (PD) and dementia with Lewy bodies are inclusions enriched in α-synuclein (α-syn), known as Lewy bodies, which are not only composed of proteins, but also a core of lipid species. PD has been thus far principally thought of as a “proteinopathy” caused by the misfolding of α-syn. However, there is a major role for certain lipids in modulating α-syn physiology in the brain and both decreased and increased membrane interactions and interactions with specific fatty acids are potential triggers for α-syn oligomerization and fibril formation. Alterations in lipid homeostasis have been observed in several brain regions that show pathology and PD should be considered not only a proteinopathy but also a lipidopathy due to the following:  1. Lipids/membranes are core components of Lewy bodies; 2. Lipid proportions in organelles affect the α-syn structure and lipid-binding properties;  3. Lipid dyshomeostasis is linked to impaired organelle function; 4. Lipid accumulation in neurons and parenchyma are associated with neuroinflammation; 5. Lipid metabolism genes have been identified as risk factors for PD.  Hence, a comprehensive analysis of the brain lipidome, in combination with genomics and proteomics, promises a more holistic view of brain chemistry and can aid in the discovery of biomarkers for diagnosing and monitoring diseases. Related Articles | Metrics

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Aggresome-aggrephagy transition process: getting closer to the functional roles of HDAC6 and BAG3 Hagen Körschgen, Christian Behl 2024, 19 (6):  1181-1182.  doi: 10.4103/1673-5374.386407 Abstract ( 125 )   PDF (608KB) ( 29 )   Save Misfolding of proteins as well as their aggregation is a major driver of age-related neurodegenerative diseases. Hence, cells have evolved sophisticated protein quality control mechanisms. Mainly the ubiquitin-proteasome-system (UPS) and the autophagosome-lysosome-system, specifically a macroautophagy pathway called “aggrephagy”, govern the disposal of aggregates. However, the cell still has to cope with fundamental challenges to keep the consequences of, e.g., age-related insufficient clearance low. The clearance of dysfunctional or misfolded proteins that can lead to toxic aggregates depends on sensing and sequestration mechanisms, which usually include molecular chaperones (e.g., heat shock protein 70 [HSP70] proteins) and co-chaperones (e.g., BAG proteins). Accordingly, the overburdening of UPS capacity or its age-related decline represents a fundamental challenge for postmitotic cells such as neurons in particular. Among other influences and effects, one hallmark of proteinopathies that is associated with neurodegeneration is precisely this overload of the UPS and the resulting accumulation of aggregation-prone proteins, such as the microtubule-associated protein tau in Alzheimer’s disease, α-synuclein in Parkinson’s disease, or superoxide dismutase 1 (SOD1) in amyotrophic lateral sclerosis. In case of a serious impairment or overload of the UPS, protein aggregates translocate to a larger, clearly defined structure called “aggresome”. This term was coined by the Kopito lab more than two decades ago (Johnston et al., 1998). The aggresome itself is assumed to be a protective cellular response that condenses potentially cytotoxic aggregates and also serves as a transit center for autophagic clearance. This perinuclear accumulation of aggregated proteins at the microtubule organizing center is clearly characterized by its vimentin cage. Accordingly, the formation of this up to several µm large structure requires a fundamental rearrangement of the intermediate vimentin cytoskeleton and represents a final condensation stage. Thus, pre-aggresomal structures emerge during its genesis. However, in spinal cord motor neurons from SOD1G85R transgenic mice, for instance, those aggresomes occur after the onset of disease symptoms. Related Articles | Metrics

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Metabolites and micronutrition in modulating amyotrophic lateral sclerosis Katerina Claud, Jun Sun 2024, 19 (6):  1183-1184.  doi: 10.4103/1673-5374.385861 Abstract ( 84 )   PDF (1324KB) ( 37 )   Save Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. The majority of ALS cases are sporadic with only about 20% of familial forms. Even in families with genetic predisposition, there is significant phenotypic variability, suggesting that ALS onset may be triggered by a combination of genetic factors, environmental factors (e.g., military service, deployments, exposures) (Beard and Kamel, 2015), lifestyle changes (e.g., cigarette smoke and dietary), and gut microbiome alteration. From our 2017 research paper demonstrating the beneficial role of the microbial metabolite butyrate (Zhang et al., 2017) to the newly approved Food and Drug Administration drug Relyvrio on September 29, 2022, the novel concepts and role of the gut microbiome and microbial metabolites in ALS pathogenesis have been slowly recognized by the neurology research field. Relyvrio is a combination of two drugs, sodium phenylbutyrate, and taurursodiol, that has been shown to reduce the rate of decline on a clinical assessment of daily functioning and is associated with longer overall survival (Paganoni et al., 2020). However, the role of sodium phenylbutyrate on intestinal function and microbiome in ALS progression was not included in the study, and research on metabolites correlated with the gut microbiome in ALS progression and treatment is still limited. A better understanding of the dynamic interactions among microbial metabolites, neuroactive metabolites, and inflammation in ALS will provide innovative insights into ALS prevention and treatment.  Related Articles | Metrics

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Smart electrochemical sensing of amyloid-beta to manage total Alzheimer’s diseases Ajeet Kaushik 2024, 19 (6):  1185-1186.  doi: 10.4103/1673-5374.385871 Abstract ( 96 )   PDF (1598KB) ( 40 )   Save Need for Alzheimer’s disease progression monitoring: Alzheimer’s disease (AD) is an irreversible progressive brain disorder that causes severe and incurable neuro-impairment. The World Health Organization estimates that 55 million people are affected by AD dementia by 2020 which may exceed 78 million by 2030 and 139 in 2050. The estimated cost to manage AD is above US$ 1.3 trillion, which will further increase to US$ 2.8 trillion by 2030. According to Alzheimer’s Diseases International and Bright Focus Foundation, the world gets a new AD patient every 3 seconds, 60% of the dementia population belongs to low and middle-income countries, and this will increase to 71% by 2050.  Related Articles | Metrics

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Insights on ZEB1-AS1: emerging roles from cancer to neurodegeneration Stephana Carelli, Federica Rey, Erika Maghraby, Cristina Cereda 2024, 19 (6):  1187-1188.  doi: 10.4103/1673-5374.385856 Abstract ( 102 )   PDF (786KB) ( 26 )   Save Implications for lncRNAs in the central nervous system: Transcriptional dysregulation is a key contributor to the pathogenesis of a wide range of diseases and long non-coding RNAs (lncRNAs) are highly expressed in the nervous system. Indeed, amongst the over 50,000 lncRNAs expressed in the human genome, more than 40% are specifically expressed in the brain where their roles in brain development, neuron functions, maintenance, and differentiation, are becoming increasingly evident (Zhou et al., 2021). In addition, some lncRNAs were found to have a role in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease, and Alzheimer’s disease, along with an interesting link to the physiological aging process (Rey et al., 2021; Zhou et al., 2021). Interestingly, RNA-sequencing analysis conducted in peripheral blood mononuclear cells of sporadic ALS patients and matched controls highlighted 293 differentially expressed lncRNAs contributing to corroborate the importance of lncRNAs in ALS (Gagliardi et al., 2018). Amongst the top ten deregulated lncRNAs identified the most dysregulated antisense of transcription-related genes was Zinc finger E-box binding homeobox 1 antisense 1 (ZEB1-AS1), antisense to the ZEB1 gene (Gagliardi et al., 2018, Garofalo et al., 2020). Related Articles | Metrics

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Empagliflozin reduces brain pathology in Alzheimer’s disease and type 2 diabetes Carmen Hierro-Bujalance, Monica Garcia-Alloza 2024, 19 (6):  1189-1190.  doi: 10.4103/1673-5374.385865 Abstract ( 85 )   PDF (730KB) ( 37 )   Save Alzheimer’s disease (AD) and type 2 diabetes (T2D): More than 55 million people suffer from dementia, and it is expected that over 150 million people will suffer from this disease by 2050. AD is the most common type of dementia and while aging remains the main risk factor to suffer it, previous studies have also shown that metabolic disorders, and T2D specifically, are also major contributors (Wang et al., 2012). The prevalence of diabetes has reached 537 million people worldwide and these figures are expected to keep rising (Ahmad et al., 2022). All things considered, both diseases are a great challenge for health professionals as well as a major social problem.  Related Articles | Metrics

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Potential role of tubulin glutamylation in neurodegenerative diseases Abdullah Md. Sheikh, Shatera Tabassum 2024, 19 (6):  1191-1192.  doi: 10.4103/1673-5374.385859 Abstract ( 123 )   PDF (1539KB) ( 43 )   Save The differentiation of neuronal stem cells into mature neurons is a complex process that involves both structural and functional changes. As cells undergo differentiation, there are notable functional changes, including the expression of various transcription factors, cytokines, and neurotransmitters. Additionally, structural changes occur as the cells develop various processes from the cell body and establish synaptic contacts with other cells. The polarization of a mature neuron (Wilson et al., 2022) is crucial for its proper functioning. It possesses processes such as an axon, which transmits signals to other neurons, and dendrites, which receive signals through synaptic contacts, forming neural circuits. These structural arrangements play a vital role because the nervous system’s primary function is to enable an organism to perform specific tasks, relying on the connections and interactions among a group of neurons that form functional neural circuits. During development, an excess of neural cells is produced compared to the number of mature neurons present in fully developed brains. Neurons that fail to establish synaptic contacts with other neurons typically undergo cell death due to a lack of tropic support, resulting in their elimination from the nervous system. This highlights the significance of such connections in neuronal functions and viability. The formation of new neural circuits continues throughout life, particularly in brain regions associated with cognitive and motor functions. Related Articles | Metrics

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Hippocampal dopamine as a key regulator for learning deficits in Parkinson’s disease Kun Wu, Shuai Liu 2024, 19 (6):  1193-1194.  doi: 10.4103/1673-5374.385860 Abstract ( 121 )   PDF (331KB) ( 46 )   Save Parkinson’s disease (PD) is a progressive neurodegenerative disorder with clinical symptoms of involuntary or uncontrollable movements such as tremors, rigidity, and incoordination. The learning deficit is largely overlooked in the past because it is generally less impaired in the early stages of PD than in Alzheimer’s disease. However, recent studies have shown a significant decline in learning in PD. In addition to a lower learning rate, PD patients require substantially more brain activity and neural networks during the learning task, indicating a reduced learning efficiency. Furthermore, memory deficits are also common in PD even without the presence of overt dementia (Aarsland et al., 2021). Given the increasing prevalence of PD worldwide and the fact that symptoms typically start out mild and get worse over time, research into the mechanism of learning deficits in PD is of great importance. Related Articles | Metrics

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Nuance of inward rectifying potassium (Kir) channel dysfunctions in neurodegenerative diseases Benjamin Garland, Linlin Ma 2024, 19 (6):  1195-1196.  doi: 10.4103/1673-5374.385870 Abstract ( 114 )   PDF (1866KB) ( 28 )   Save Neurodegenerative disorders are highly prevalent and diverse in nature. Their manifestation largely depends on the cell types involved, with aberrant inflammatory episodes progressively inducing a constellation of phenotypes that are classified into specific diseases based on their neuropathological traits. The two most prevalent neurodegenerative diseases worldwide, Alzheimer’s disease (AD) and Parkinson’s disease (PD), for example, share notable similarities, yet they differ in terms of the specific cell types lost within the central nervous system (CNS). The significant and progressive loss of cortical and certain subcortical neurons in various regions is a major defining trait of AD. In contrast, the specific loss of dopaminergic neurons (DA) within the substantial nigra pars compacta (SNpc) is sufficient to cause motor symptoms associated with PD. Another devastating condition arising from neurodegeneration within the CNS, amyotrophic lateral sclerosis (ALS), results in the progressive death of upper and lower motor neurons. This degeneration originates in oligodendrocytes, whose defective myelination abilities lead to the denervation of the anterior horn, aggravating motor neuron death. In the case of Huntington’s disease (HD), early motor symptoms are generally attributed to the selective loss of D2-medium spiny neurons. These multifactorial diseases involve diverse risk factors and complex pathobiological mechanisms that are intertwined and convoluted. Intriguingly, a growing body of research in recent years has associated inward-rectifying potassium (Kir) channels with several neurodegenerative diseases such as AD (Akyuz et al., 2020), ALS (Peric et al., 2021), HD (Tong et al., 2014) and PD (Liu et al., 2022).  Related Articles | Metrics

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Influence of aging, mitochondrial dysfunction, and inflammation on Parkinson’s disease Davide Cossu, Nobutaka Hattori 2024, 19 (6):  1197-1198.  doi: 10.4103/1673-5374.385873 Abstract ( 97 )   PDF (1854KB) ( 41 )   Save Aging is associated with chronic form of inflammation called inflammaging, which results from immune system changes. Inflammaging plays a crucial role in the pathogenesis of various neurodegenerative diseases (Dabravolski et al., 2022). Moreover, aging-related inflammation can be triggered by disrupted mitophagy, where the accumulation of molecular patterns associated with mitochondrial damage in the cytosol leads to the production of inflammatory cytokines and activation of the immune response. In our recent research, we investigated the impact of aging and mitochondrial dysfunction on neuroinflammation using a model of central nervous system (CNS) neuroinflammation in mice that lack genes associated with familial Parkinson’s disease (PD; Figure 1). Related Articles | Metrics

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Investigating epithelial-neuronal signaling contribution in visceral pain through colon organoid-dorsal root ganglion neuron co-cultures Francesco Margiotta, Lorenzo Di Cesare Mannelli, Antonino Morabito, Carla Ghelardini, Elena Lucarini 2024, 19 (6):  1199-1200.  doi: 10.4103/1673-5374.386403 Abstract ( 123 )   PDF (2586KB) ( 56 )   Save Abdominal pain is a common symptom associated with irritable bowel syndrome and inflammatory bowel diseases (IBDs), affecting about 20% of the global population (Grundy et al., 2019). Current pain therapies are poorly effective on visceral pain of intestinal origin and present several side effects, hence the need to identify novel molecular and cellular targets for drug development. The pathophysiology of visceral-abdominal pain, which often originates from the colorectal region, involves several actors, including the gut microbiome, intestinal epithelium, immune system, and nervous system at different levels through the gut-brain axis (Lucarini et al., 2020, 2022; Najjar et al., 2020). Nociceptive stimuli from the bowel to the central nervous system are mainly encoded by spinal afferents, whose cell bodies reside within the thoracolumbar and lumbosacral dorsal root ganglia (DRGs; Grundy et al., 2019). Visceral pain results from an altered neuronal transduction and transmission of stimuli generated within the gut. Current evidence attests that visceral hypersensitivity is a complex phenomenon, consisting of multiple mechanisms, with immune cells playing a role in hypersensitizing colon afferents through the release of different mediators (Grundy et al., 2019). However, pain is also reported without any inflammatory status, suggesting factors other than the inflammatory/immune signaling in driving pain transmission/persistence. Related Articles | Metrics

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SCFD1 in amyotrophic lateral sclerosis: reconciling a genetic association with in vivo functional analysis Ruben J. Cauchi 2024, 19 (6):  1201-1202.  doi: 10.4103/1673-5374.386411 Abstract ( 114 )   PDF (5045KB) ( 80 )   Save Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons, resulting in muscle weakness and spasticity, eventually leading to death due to respiratory failure. Analyses by our group of a case-control cohort from an isolated island population have found that genetics plays a significant role in disease etiology (Farrugia Wismayer et al., 2023). In addition to rare variants that cause familial monogenic forms of the disease, genetic variants that are commonly found in the population have also been associated with disease risk. To this end, the latest landmark cross-ancestry genome-wide association study (GWAS) identified multiple risk loci in patients with sporadic ALS or those without a family history of the disease (van Rheenen et al., 2021). Top-ranking loci identified in this study included the Sec1 Family Domain Containing 1 (SCFD1) gene and the uncoordinated 13 homolog A (UNC13A) gene based on association with the rs229195 and rs12608932 variants, respectively. Interestingly, although proteins encoded by SCFD1 and UNC13A have similar functions in vesicle transport and disruption of this pathway is well known to induce motor neuron degeneration (Mead et al., 2022), establishing a relationship between these risk genes and ALS pathophysiology has been challenging. This is nonetheless imperative because risk loci can be therapeutically targeted in a broad spectrum of ALS patients in addition to pre-symptomatic individuals with a higher ALS risk. Notably, recent studies have attempted to discover a potential link between major GWAS-identified risk loci and disease mechanism (Brown et al., 2022; Ma et al., 2022; Borg et al., 2023). For UNC13A, mis-splicing of its messenger RNA (mRNA) transcript in ALS patients was found to result in lower protein levels with serious consequences for synaptic maintenance (Brown et al., 2022; Ma et al., 2022). Making use of a pre-clinical model, we have shown that synaptic deficits and the resulting decline in neuromuscular function can also result from reduced levels of SCFD1 (Borg et al., 2023; Figure 1). Importantly, disease predisposition from loss of UNC13A or SCFD1 function may be intimately linked to protein misfolding and aggregation which remains a hallmark feature of ALS (Mead et al., 2022). Risk variants in the UNC13A locus are thought to be consequential in the absence of functional nuclear TDP-43 (Brown et al., 2022; Ma et al., 2022), a main constituent of cytoplasmic protein aggregates in ALS patients (Mead et al., 2022). A general downregulation of protein folding pathways may explain why the loss of SCFD1 leads to a decline in neuromuscular function (Borg et al., 2023). Related Articles | Metrics

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Neural plasticity in Parkinson’s disease: a neuroimaging perspective Christina Andica, Koji Kamagata 2024, 19 (6):  1203-1205.  doi: 10.4103/1673-5374.386404 Abstract ( 82 )   PDF (1829KB) ( 21 )   Save Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized primarily by classical motor signs of bradykinesia, rigidity, tremors, and postural instability usually manifesting unilaterally or at least asymmetrically. The disease involves a loss of dopaminergic neurons projecting from the substantia nigra pars compacta to the dorsal striatum, and the presence of Lewy bodies and Lewy neurites (intraneuronal inclusions composed of misfolded and aggregated α-synuclein; Tagliaferro and Burke, 2016). Literature suggests that PD symptoms appear only after a substantial loss of dopaminergic neurons, i.e., around 50–70% of striatal dopaminergic terminals and 30% of substantia nigra dopaminergic neurons (Tagliaferro and Burke, 2016). Several PD subtypes based on the presentation, such as the tremor-dominant (TD) type and PD with right-side dominant symptoms, have been found to demonstrate a better prognosis and a less severe clinical picture than PD-related postural instability and gait disorders and left-dominant PD, respectively. In this regard, the neuronal compensatory response is considered responsible for delaying or reducing the severity of PD-related symptoms. Furthermore, histopathological research conducted on the brain tissues of PD mice models, which express the A53T mutation in the α-synuclein gene, demonstrated increased axonal arborization and collateralization in the white matter (Schechter et al., 2020). These findings suggest that α-synuclein is essential in promoting axonal growth during the early stages of the disease (Schechter et al., 2020). Similarly, studies involving brain tissues of human PD patients showed adaptive changes in motor circuits within the brain characterized by axonal collateralization, as well as an increase in the size and density of oligodendrocytes (Fu et al., 2022). Therefore, expanding our knowledge of neuroplasticity within the cortical-basal ganglia-thalamocortical circuits may have valuable implications in the development of innovative therapies and early-stage diagnostic approaches for PD. However, the current literature on PD does not adequately address the evidence regarding neural plasticity, presumably because of the limitations of in vivo imaging techniques in accurately capturing microstructural changes in brain tissue. This perspective article aimed to outline the utilization of advanced magnetic resonance imaging (MRI) techniques, including diffusion MRI and myelin imaging, to assess the microstructure of brain tissue to elucidate neural plasticity in Parkinson’s disease. Furthermore, the article explored potential future prospects in this field. Related Articles | Metrics

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The bumpy road of purinergic inhibitors to clinical application in immune-mediated diseases Matthias T. Wyss, Christine Heuer, Marina Herwerth 2024, 19 (6):  1206-1211.  doi: 10.4103/1673-5374.386405 Abstract ( 83 )   PDF (791KB) ( 70 )   Save Purinergic signaling plays important roles throughout the body in the regulation of organ functions during and following the disruption of homeostasis. This is also reflected by the widespread expression of two families of purinergic receptors (P1 and P2) with numerous subtypes. In the last few decades, there has been increasing evidence that purinergic signaling plays an important role in the regulation of immune functions. Mainly, signals mediated by P2 receptors have been shown to contribute to immune system-mediated pathologies. Thus, interference with P2 receptors may be a promising strategy for the modulation of immune responses. Although only a few clinical studies have been conducted in isolated entities with limited success, preclinical work suggests that the use of P2 receptor inhibitors may bear some promise in various autoimmune diseases. Despite the association of P2 receptors with several disorders from this field, the use of P2 receptor antagonists in clinical therapy is still very scarce. In this narrative review, we briefly review the involvement of the purinergic system in immunological responses and clinical studies on the effect of purinergic inhibition on autoimmune processes. We then open the aperture a bit and show some preclinical studies demonstrating a potential effect of purinergic blockade on autoimmune events. Using suramin, a non-specific purinergic inhibitor, as an example, we further show that off-target effects could be responsible for observed effects in immunological settings, which may have interesting implications. Overall, we believe that it is worthwhile to further investigate this hitherto underexplored area. Related Articles | Metrics

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Long non-coding RNAs with essential roles in neurodegenerative disorders Wandi Xiong, Lin Lu, Jiali Li 2024, 19 (6):  1212-1220.  doi: 10.4103/1673-5374.385850 Abstract ( 176 )   PDF (2273KB) ( 112 )   Save Recently, with the advent of high-resolution and high-throughput sequencing technologies, an increasing number of long non-coding RNAs (lncRNAs) have been found to be involved in the regulation of neuronal function in the central nervous system with specific spatiotemporal patterns, across different neurodegenerative diseases. However, the underlying mechanisms of lncRNAs during neurodegeneration remain poorly understood. This review provides an overview of the current knowledge of the biology of lncRNAs and focuses on introducing the latest identified roles, regulatory mechanisms, and research status of lncRNAs in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Finally, this review discusses the potential values of lncRNAs as diagnostic biomarkers and therapeutic targets for neurodegenerative diseases, hoping to provide broader implications for developing effective treatments. Related Articles | Metrics

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Tau truncation in the pathogenesis of Alzheimer’s disease: a narrative review Dandan Chu, Xingyue Yang, Jing Wang, Yan Zhou, Jin-Hua Gu, Jin Miao, Feng Wu, Fei Liu 2024, 19 (6):  1221-1232.  doi: 10.4103/1673-5374.385853 Abstract ( 345 )   PDF (2278KB) ( 373 )   Save Alzheimer’s disease is characterized by two major neuropathological hallmarks—the extracellular β-amyloid plaques and intracellular neurofibrillary tangles consisting of aggregated and hyperphosphorylated Tau protein. Recent studies suggest that dysregulation of the microtubule-associated protein Tau, especially specific proteolysis, could be a driving force for Alzheimer’s disease neurodegeneration. Tau physiologically promotes the assembly and stabilization of microtubules, whereas specific truncated fragments are sufficient to induce abnormal hyperphosphorylation and aggregate into toxic oligomers, resulting in them gaining prion-like characteristics. In addition, Tau truncations cause extensive impairments to neural and glial cell functions and animal cognition and behavior in a fragment-dependent manner. This review summarizes over 60 proteolytic cleavage sites and their corresponding truncated fragments, investigates the role of specific truncations in physiological and pathological states of Alzheimer’s disease, and summarizes the latest applications of strategies targeting Tau fragments in the diagnosis and treatment of Alzheimer’s disease.  Related Articles | Metrics

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Blood-brain barrier pathology in cerebral small vessel disease Ruxue Jia, Gemma Solé-Guardia, Amanda J. Kiliaan 2024, 19 (6):  1233-1240.  doi: 10.4103/1673-5374.385864 Abstract ( 112 )   PDF (1828KB) ( 158 )   Save Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the elderly. Although at first it was considered innocuous, small vessel disease is nowadays regarded as one of the major vascular causes of dementia. Radiological signs of small vessel disease include small subcortical infarcts, white matter magnetic resonance imaging hyperintensities, lacunes, enlarged perivascular spaces, cerebral microbleeds, and brain atrophy; however, great heterogeneity in clinical symptoms is observed in small vessel disease patients. The pathophysiology of these lesions has been linked to multiple processes, such as hypoperfusion, defective cerebrovascular reactivity, and blood-brain barrier dysfunction. Notably, studies on small vessel disease suggest that blood-brain barrier dysfunction is among the earliest mechanisms in small vessel disease and might contribute to the development of the hallmarks of small vessel disease. Therefore, the purpose of this review is to provide a new foundation in the study of small vessel disease pathology. First, we discuss the main structural domains and functions of the blood-brain barrier. Secondly, we review the most recent evidence on blood-brain barrier dysfunction linked to small vessel disease. Finally, we conclude with a discussion on future perspectives and propose potential treatment targets and interventions. Related Articles | Metrics

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Microglial response to aging and neuroinflammation in the development of neurodegenerative diseases Tingting Han, Yuxiang Xu, Lin Sun, Makoto Hashimoto, Jianshe Wei 2024, 19 (6):  1241-1248.  doi: 10.4103/1673-5374.385845 Abstract ( 447 )   PDF (1602KB) ( 291 )   Save Cellular senescence and chronic inflammation in response to aging are considered to be indicators of brain aging; they have a great impact on the aging process and are the main risk factors for neurodegeneration. Reviewing the microglial response to aging and neuroinflammation in neurodegenerative diseases will help understand the importance of microglia in neurodegenerative diseases. This review describes the origin and function of microglia and focuses on the role of different states of the microglial response to aging and chronic inflammation on the occurrence and development of neurodegenerative diseases, including Alzheimer’s disease, Huntington’s chorea, and Parkinson’s disease. This review also describes the potential benefits of treating neurodegenerative diseases by modulating changes in microglial states. Therefore, inducing a shift from the neurotoxic to neuroprotective microglial state in neurodegenerative diseases induced by aging and chronic inflammation holds promise for the treatment of neurodegenerative diseases in the future. Related Articles | Metrics

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Intranasal administration of stem cell-derived exosomes for central nervous system diseases Shuho Gotoh, Masahito Kawabori, Miki Fujimura 2024, 19 (6):  1249-1255.  doi: 10.4103/1673-5374.385875 Abstract ( 179 )   PDF (19442KB) ( 67 )   Save Exosomes, lipid bilayer-enclosed small cellular vesicles, are actively secreted by various cells and play crucial roles in intercellular communication. These nanosized vesicles transport internalized proteins, mRNA, miRNA, and other bioactive molecules. Recent findings have provided compelling evidence that exosomes derived from stem cells hold great promise as a therapeutic modality for central nervous system disorders. These exosomes exhibit multifaceted properties including anti-apoptotic, anti-inflammatory, neurogenic, and vasculogenic effects. Furthermore, exosomes offer several advantages over stem cell therapy, such as high preservation capacity, low immunogenicity, the ability to traverse the blood-brain barrier, and the potential for drug encapsulation. Consequently, researchers have turned their attention to exosomes as a novel therapeutic avenue. Nonetheless, akin to the limitations of stem cell treatment, the limited accumulation of exosomes in the injured brain poses a challenge to their clinical application. To overcome this hurdle, intranasal administration has emerged as a non-invasive and efficacious route for delivering drugs to the central nervous system. By exploiting the olfactory and trigeminal nerve axons, this approach enables the direct transport of therapeutics to the brain while bypassing the blood-brain barrier. Notably, exosomes, owing to their small size, can readily access the nerve pathways using this method. As a result, intranasal administration has gained increasing recognition as an optimal therapeutic strategy for exosome-based treatments. In this comprehensive review, we aim to provide an overview of both basic and clinical research studies investigating the intranasal administration of exosomes for the treatment of central nervous system diseases. Furthermore, we elucidate the underlying therapeutic mechanisms and offer insights into the prospect of this approach. Related Articles | Metrics

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Dysregulation of RNA modification systems in clinical populations with neurocognitive disorders Helen M. Knight, Merve Demirbugen Öz, Adriana PerezGrovas-Saltijeral 2024, 19 (6):  1256-1261.  doi: 10.4103/1673-5374.385858 Abstract ( 89 )   PDF (6286KB) ( 329 )   Save Related Articles | Metrics

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Amyloid-beta and tau protein beyond Alzheimer’s disease Morteza Abyadeh, Vivek Gupta, Joao A. Paulo, Arezoo Gohari Mahmoudabad, Sina Shadfar, Shahab Mirshahvaladi, Veer Gupta, Christine T.O. Nguyen, David I. Finkelstein, Yuyi You, Paul A. Haynes, Ghasem H. Salekdeh, Stuart L. Graham, Mehdi Mirzaei 2024, 19 (6):  1262-1276.  doi: 10.4103/1673-5374.386406 Abstract ( 150 )   PDF (5356KB) ( 305 )   Save The aggregation of amyloid-beta peptide and tau protein dysregulation are implicated to play key roles in Alzheimer’s disease pathogenesis and are considered the main pathological hallmarks of this devastating disease. Physiologically, these two proteins are produced and expressed within the normal human body. However, under pathological conditions, abnormal expression, post-translational modifications, conformational changes, and truncation can make these proteins prone to aggregation, triggering specific disease-related cascades. Recent studies have indicated associations between aberrant behavior of amyloid-beta and tau proteins and various neurological diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, as well as retinal neurodegenerative diseases like Glaucoma and age-related macular degeneration. Additionally, these proteins have been linked to cardiovascular disease, cancer, traumatic brain injury, and diabetes, which are all leading causes of morbidity and mortality. In this comprehensive review, we provide an overview of the connections between amyloid-beta and tau proteins and a spectrum of disorders. Related Articles | Metrics

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The dual role of striatal interneurons: circuit modulation and trophic support for the basal ganglia Elliot Wegman, Marlena Wosiski-Kuhn, Yu Luo 2024, 19 (6):  1277-1283.  doi: 10.4103/1673-5374.382987 Abstract ( 84 )   PDF (690KB) ( 106 )   Save Striatal interneurons play a key role in modulating striatal-dependent behaviors, including motor activity and reward and emotional processing. Interneurons not only provide modulation to the basal ganglia circuitry under homeostasis but are also involved in changes to plasticity and adaptation during disease conditions such as Parkinson’s or Huntington’s disease. This review aims to summarize recent findings regarding the role of striatal cholinergic and GABAergic interneurons in providing circuit modulation to the basal ganglia in both homeostatic and disease conditions. In addition to direct circuit modulation, striatal interneurons have also been shown to provide trophic support to maintain neuron populations in adulthood. We discuss this interesting and novel role of striatal interneurons, with a focus on the maintenance of adult dopaminergic neurons from interneuron-derived sonic-hedgehog.    Related Articles | Metrics

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Molecular mechanisms underlying microglial sensing and phagocytosis in synaptic pruning Anran Huo, Jiali Wang, Qi Li, Mengqi Li, Yuwan Qi, Qiao Yin, Weifeng Luo, Jijun Shi, Qifei Cong 2024, 19 (6):  1284-1290.  doi: 10.4103/1673-5374.385854 Abstract ( 923 )   PDF (1444KB) ( 295 )   Save Microglia are the main non-neuronal cells in the central nervous system that have important roles in brain development and functional connectivity of neural circuits. In brain physiology, highly dynamic microglial processes are facilitated to sense the surrounding environment and stimuli. Once the brain switches its functional states, microglia are recruited to specific sites to exert their immune functions, including the release of cytokines and phagocytosis of cellular debris. The crosstalk of microglia between neurons, neural stem cells, endothelial cells, oligodendrocytes, and astrocytes contributes to their functions in synapse pruning, neurogenesis, vascularization, myelination, and blood-brain barrier permeability. In this review, we highlight the neuron-derived “find-me,” “eat-me,” and “don’t eat-me” molecular signals that drive microglia in response to changes in neuronal activity for synapse refinement during brain development. This review reveals the molecular mechanism of neuron-microglia interaction in synaptic pruning and presents novel ideas for the synaptic pruning of microglia in disease, thereby providing important clues for discovery of target drugs and development of nervous system disease treatment methods targeting synaptic dysfunction.  Related Articles | Metrics

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Neuroprotective effects of chaperone-mediated autophagy in neurodegenerative diseases Qi Jia, Jin Li, Xiaofeng Guo, Yi Li, You Wu, Yuliang Peng, Zongping Fang, Xijing Zhang 2024, 19 (6):  1291-1298.  doi: 10.4103/1673-5374.385848 Abstract ( 96 )   PDF (1977KB) ( 79 )   Save Chaperone-mediated autophagy is one of three types of autophagy and is characterized by the selective degradation of proteins. Chaperone-mediated autophagy contributes to energy balance and helps maintain cellular homeostasis, while providing nutrients and support for cell survival. Chaperone-mediated autophagy activity can be detected in almost all cells, including neurons. Owing to the extreme sensitivity of neurons to their environmental changes, maintaining neuronal homeostasis is critical for neuronal growth and survival. Chaperone-mediated autophagy dysfunction is closely related to central nervous system diseases. It has been shown that neuronal damage and cell death are accompanied by chaperone-mediated autophagy dysfunction. Under certain conditions, regulation of chaperone-mediated autophagy activity attenuates neurotoxicity. In this paper, we review the changes in chaperone-mediated autophagy in neurodegenerative diseases, brain injury, glioma, and autoimmune diseases. We also summarize the most recent research progress on chaperone-mediated autophagy regulation and discuss the potential of chaperone-mediated autophagy as a therapeutic target for central nervous system diseases. Related Articles | Metrics

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The secondary injury cascade after spinal cord injury: an analysis of local cytokine/chemokine regulation#br# Daniel J. Hellenbrand, Charles M. Quinn, Zachariah J. Piper, Ryan T. Elder, Raveena R. Mishra, Taylor L. Marti, Phoebe M. Omuro, Rylie M. Roddick, Jae Sung Lee, William L. Murphy, Amgad S. Hanna 2024, 19 (6):  1308-1317.  doi: 10.4103/1673-5374.385849 Abstract ( 262 )   PDF (2738KB) ( 227 )   Save After spinal cord injury, there is an extensive infiltration of immune cells, which exacerbates the injury and leads to further neural degeneration. Therefore, a major aim of current research involves targeting the immune response as a treatment for spinal cord injury. Although much research has been performed analyzing the complex inflammatory process following spinal cord injury, there remain major discrepancies within previous literature regarding the timeline of local cytokine regulation. The objectives of this study were to establish an overview of the timeline of cytokine regulation for 2 weeks after spinal cord injury, identify sexual dimorphisms in terms of cytokine levels, and determine local cytokines that significantly change based on the severity of spinal cord injury. Rats were inflicted with either a mild contusion, moderate contusion, severe contusion, or complete transection, 7 mm of spinal cord centered on the injury was harvested at varying times post-injury, and tissue homogenates were analyzed with a Cytokine/Chemokine 27-Plex assay. Results demonstrated pro-inflammatory cytokines including tumor necrosis factor α, interleukin-1β, and interleukin-6 were all upregulated after spinal cord injury, but returned to uninjured levels within approximately 24 hours post-injury, while chemokines including monocyte chemoattractant protein-1 remained upregulated for days post-injury. In contrast, several anti-inflammatory cytokines and growth factors including interleukin-10 and vascular endothelial growth factor were downregulated by 7 days post-injury. After spinal cord injury, tissue inhibitor of metalloproteinase-1, which specifically affects astrocytes involved in glial scar development, increased more than all other cytokines tested, reaching 26.9-fold higher than uninjured rats. After a mild injury, 11 cytokines demonstrated sexual dimorphisms; however, after a severe contusion only leptin levels were different between female and male rats. In conclusion, pro-inflammatory cytokines initiate the inflammatory process and return to baseline within hours post-injury, chemokines continue to recruit immune cells for days post-injury, while anti-inflammatory cytokines are downregulated by a week post-injury, and sexual dimorphisms observed after mild injury subsided with more severe injuries. Results from this work define critical chemokines that influence immune cell infiltration and important cytokines involved in glial scar development after spinal cord injury, which are essential for researchers developing treatments targeting secondary damage after spinal cord injury. Related Articles | Metrics

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Enhancement of endogenous midbrain neurogenesis by microneurotrophin BNN-20 after neural progenitor grafting in a mouse model of nigral degeneration Theodora Mourtzi, Nasia Antoniou, Christina Dimitriou, Panagiotis Gkaravelas, Georgia Athanasopoulou, Panagiota Nti Kostantzo, Olga Stathi, Efthymia Theodorou, Maria Anesti, Rebecca Matsas, Fevronia Angelatou, Georgia Kouroupi, Ilias Kazanis 2024, 19 (6):  1318-1324.  doi: 10.4103/1673-5374.385314 Abstract ( 115 )   PDF (20186KB) ( 18 )   Save We have previously shown the neuroprotective and pro-neurogenic activity of microneurotrophin BNN-20 in the substantia nigra of the “weaver” mouse, a model of progressive nigrostriatal degeneration. Here, we extended our investigation in two clinically-relevant ways. First, we assessed the effects of BNN-20 on human induced pluripotent stem cell-derived neural progenitor cells and neurons derived from healthy and parkinsonian donors. Second, we assessed if BNN-20 can boost the outcome of mouse neural progenitor cell intranigral transplantations in weaver mice, at late stages of degeneration. We found that BNN-20 has limited direct effects on cultured human induced pluripotent stem cell-derived neural progenitor cells, marginally enhancing their differentiation towards neurons and partially reversing the pathological phenotype of dopaminergic neurons generated from parkinsonian donors. In agreement, we found no effects of BNN-20 on the mouse neural progenitor cells grafted in the substantia nigra of weaver mice. However, the graft strongly induced an endogenous neurogenic response throughout the midbrain, which was significantly enhanced by the administration of microneurotrophin BNN-20. Our results provide straightforward evidence of the existence of an endogenous midbrain neurogenic system that can be specifically strengthened by BNN-20. Interestingly, the lack of major similar activity on cultured human induced pluripotent stem cell-derived neural progenitors and their progeny reveals the in vivo specificity of the aforementioned pro-neurogenic effect. Related Articles | Metrics

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Mitochondrial transplantation confers protection against the effects of ischemic stroke by repressing microglial pyroptosis and promoting neurogenesis Li Sun, Zhaoyan Zhao, Jing Guo, Yuan Qin, Qian Yu, Xiaolong Shi, Fei Guo, Haiqin Zhang, Xude Sun, Changjun Gao, Qian Yang 2024, 19 (6):  1325-1335.  doi: 10.4103/1673-5374.385313 Abstract ( 665 )   PDF (21142KB) ( 104 )   Save Transferring healthy and functional mitochondria to the lateral ventricles confers neuroprotection in a rat model of ischemia-reperfusion injury. Autologous mitochondrial transplantation is also beneficial in pediatric patients with cardiac ischemia-reperfusion injury. Thus, transplantation of functional exogenous mitochondria may be a promising therapeutic approach for ischemic disease. To explore the neuroprotective effect of mitochondria transplantation and determine the underlying mechanism in ischemic stroke, in this study we established a photo-thrombosis-induced mouse model of focal ischemia and administered freshly isolated mitochondria via the tail vein or to the injury site (in situ). Animal behavior tests, immunofluorescence staining, 2,3,5-triphenyltetrazolium chloride (TTC) staining, mRNA-seq, and western blotting were used to assess mouse anxiety and memory, cortical infarct area, pyroptosis, and neurogenesis, respectively. Using bioinformatics analysis, western blotting, co-immunoprecipitation, and mass spectroscopy, we identified S100 calcium binding protein A9 (S100A9) as a potential regulator of mitochondrial function and determined its possible interacting proteins. Interactions between exogenous and endogenous mitochondria, as well as the effect of exogenous mitochondria on recipient microglia, were assessed in vitro. Our data showed that: (1) mitochondrial transplantation markedly reduced mortality and improved emotional and cognitive function, as well as reducing infarct area, inhibiting pyroptosis, and promoting cortical neurogenesis; (2) microglial expression of S100A9 was markedly increased by ischemic injury and regulated mitochondrial function; (3) in vitro, exogenous mitochondria enhanced mitochondrial function, reduced redox stress, and regulated microglial polarization and pyroptosis by fusing with endogenous mitochondria; and (4) S100A9 promoted internalization of exogenous mitochondria by the microglia, thereby amplifying their pro-proliferation and anti-inflammatory effects. Taken together, our findings show that mitochondrial transplantation protects against the deleterious effects of ischemic stroke by suppressing pyroptosis and promoting neurogenesis, and that S100A9 plays a vital role in promoting internalization of exogenous mitochondria. Related Articles | Metrics

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Exercise-with-melatonin therapy improves sleep disorder and motor dysfunction in a rat model of ischemic stroke Haitao Zhao, Tong Zhang, Haojie Zhang, Yunlei Wang, Lingna Cheng 2024, 19 (6):  1336-1343.  doi: 10.4103/1673-5374.385844 Abstract ( 154 )   PDF (27466KB) ( 43 )   Save Exercise-with-melatonin therapy has complementary and synergistic effects on spinal cord injury and Alzheimer’s disease, but its effect on stroke is still poorly understood. In this study, we established a rat model of ischemic stroke by occluding the middle cerebral artery for 60 minutes. We treated the rats with exercise and melatonin therapy for 7 consecutive days. Results showed that exercise-with-melatonin therapy significantly prolonged sleep duration in the model rats, increased delta power values, and regularized delta power rhythm. Additionally, exercise-with-melatonin therapy improved coordination, endurance, and grip strength, as well as learning and memory abilities. At the same time, it led to higher hippocampal CA1 neuron activity and postsynaptic density thickness and lower expression of glutamate receptor 2 than did exercise or melatonin therapy alone. These findings suggest that exercise-with-melatonin therapy can alleviate sleep disorder and motor dysfunction by increasing glutamate receptor 2 protein expression and regulating hippocampal CA1 synaptic plasticity. Related Articles | Metrics

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Post-acute ischemic stroke hyperglycemia aggravates destruction of the blood-brain barrier Tianqi Xu, Jianhong Yang, Yao Xu, Xiaofeng Wang, Xiang Gao, Jie Sun, Chenhui Zhou, Yi Huang 2024, 19 (6):  1344-1350.  doi: 10.4103/1673-5374.385851 Abstract ( 148 )   PDF (9676KB) ( 79 )   Save Post-acute ischemic stroke hyperglycemia increases the risk of hemorrhagic transformation, which is associated with blood-brain barrier disruption. Brain microvascular endothelial cells are a major component of the blood-brain barrier. Intercellular mitochondrial transfer has emerged as a novel paradigm for repairing cells with mitochondrial dysfunction. In this study, we first investigated whether mitochondrial transfer exists between brain microvascular endothelial cells, and then investigated the effects of post-acute ischemic stroke hyperglycemia on mitochondrial transfer between brain microvascular endothelial cells. We found that healthy brain microvascular endothelial cells can transfer intact mitochondria to oxygen glucose deprivation-injured brain microvascular endothelial cells. However, post-oxygen glucose deprivation hyperglycemia hindered mitochondrial transfer and exacerbated mitochondrial dysfunction. We established an in vitro brain microvascular endothelial cell model of the blood-brain barrier. We found that post-acute ischemic stroke hyperglycemia reduced the overall energy metabolism levels of brain microvascular endothelial cells and increased permeability of the blood-brain barrier. In a clinical study, we retrospectively analyzed the relationship between post-acute ischemic stroke hyperglycemia and the severity of hemorrhagic transformation. We found that post-acute ischemic stroke hyperglycemia serves as an independent predictor of severe hemorrhagic transformation. These findings suggest that post-acute ischemic stroke hyperglycemia can aggravate disruption of the blood-brain barrier by inhibiting mitochondrial transfer.  Related Articles | Metrics

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Vibration-reduced anxiety-like behavior relies on ameliorating abnormalities of the somatosensory cortex and medial prefrontal cortex Afzal Misrani, Sidra Tabassum, Tintin Wang, Huixian Huang, Jinxiang Jiang, Hongjun Diao, Yanping Zhao, Zhen Huang, Shaohua Tan, Cheng Long, Li Yang 2024, 19 (6):  1351-1359.  doi: 10.4103/1673-5374.385840 Abstract ( 555 )   PDF (9173KB) ( 201 )   Save Tibetan singing bowls emit low-frequency sounds and produce perceptible harmonic tones and vibrations through manual tapping. The sounds the singing bowls produce have been shown to enhance relaxation and reduce anxiety. However, the underlying mechanism remains unclear. In this study, we used chronic restraint stress or sleep deprivation to establish mouse models of anxiety that exhibit anxiety-like behaviors. We then supplied treatment with singing bowls in a bottomless cage placed on the top of a cushion. We found that unlike in humans, the combination of harmonic tones and vibrations did not improve anxiety-like behaviors in mice, while individual vibration components did. Additionally, the vibration of singing bowls increased the level of N-methyl-D-aspartate receptor 1 in the somatosensory cortex and prefrontal cortex of the mice, decreased the level of γ-aminobutyric acid A (GABA) receptor α 1 subtype, reduced the level of CaMKII in the prefrontal cortex, and increased the number of GABAergic interneurons. At the same time, electrophysiological tests showed that the vibration of singing bowls significantly reduced the abnormal low-frequency gamma oscillation peak frequency in the medial prefrontal cortex caused by stress restraint pressure and sleep deprivation. Results from this study indicate that the vibration of singing bowls can alleviate anxiety-like behaviors by reducing abnormal molecular and electrophysiological events in somatosensory and medial prefrontal cortex. Related Articles | Metrics

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Upregulation of circ0000381 attenuates microglial/macrophage pyroptosis after spinal cord injury Yan Zhang, Wenkai Zhang, Tao Liu, Ziqian Ma, Wenxiu Zhang, Yun Guan, Xueming Chen 2024, 19 (6):  1360-1366.  doi: 10.4103/1673-5374.386399 Abstract ( 128 )   PDF (50867KB) ( 38 )   Save Neuroinflammation exacerbates secondary damage after spinal cord injury, while microglia/macrophage pyroptosis is important to neuroinflammation. Circular RNAs (circRNAs) play a role in the central nervous system. However, the functional role and mechanism of circRNAs in regulating microglia/macrophage pyroptosis after spinal cord injury are still poorly studied. In the present study, we detected microglia/macrophage pyroptosis in a female rat model of spinal cord injury, along with upregulated levels of circ0000381 in the spinal cord. Our further experimental results suggest that circ0000381 may function as a sponge to sequester endogenous microRNA423-3p (miR-423-3p), which can increase the expression of NOD-like receptor 3 (NLRP3), a pyroptosis marker. Therefore, upregulation of circ0000381 may be a compensatory change after spinal cord injury to attenuate microglia/macrophage pyroptosis. Indeed, knockdown of circ0000381 expression exacerbated microglia/macrophage pyroptosis. Collectively, our findings provide novel evidence for the upregulation of circ0000381, which may serve as a neuroprotective mechanism to attenuate microglia/macrophage pyroptosis after spinal cord injury. Accordingly, circ0000381 may be a novel therapeutic target for the treatment of spinal cord injury. Related Articles | Metrics

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Prediction of cell-cell communication patterns of dorsal root ganglion cells: single-cell RNA sequencing data analysis Yanna Lian, Cheng Wu, Li Liu, Xiangyao Li 2024, 19 (6):  1367-1374.  doi: 10.4103/1673-5374.384067 Abstract ( 218 )   PDF (33424KB) ( 104 )   Save Dorsal root ganglion neurons transmit peripheral somatic information to the central nervous system, and dorsal root ganglion neuron excitability affects pain perception. Dorsal root ganglion stimulation is a new approach for managing pain sensation. Knowledge of the cell-cell communication among dorsal root ganglion cells may help in the development of new pain and itch management strategies. Here, we used the single-cell RNA-sequencing (scRNA-seq) database to investigate intercellular communication networks among dorsal root ganglion cells. We collected scRNA-seq data from six samples from three studies, yielding data on a total of 17,766 cells. Based on genetic profiles, we identified satellite glial cells, Schwann cells, neurons, vascular endothelial cells, immune cells, fibroblasts, and vascular smooth muscle cells. Further analysis revealed that eight types of dorsal root ganglion neurons mediated proprioceptive, itch, touch, mechanical, heat, and cold sensations. Moreover, we predicted several distinct forms of intercellular communication among dorsal root ganglion cells, including cell-cell contact, secreted signals, extracellular matrix, and neurotransmitter-mediated signals. The data mining predicted that Mrgpra3-positive neurons robustly express the genes encoding the adenosine Adora2b (A2B) receptor and glial cell line-derived neurotrophic factor family receptor alpha 1 (GFRα-1). Our immunohistochemistry results confirmed the coexpression of the A2B receptor and GFRα-1. Intrathecal injection of the A2B receptor antagonist PSB-603 effectively prevented histamine-induced scratching behaviour in a dose-dependent manner. Our results demonstrate the involvement of the A2B receptor in the modulation of itch sensation. Furthermore, our findings provide insight into dorsal root ganglion cell-cell communication patterns and mechanisms. Our results should contribute to the development of new strategies for the regulation of dorsal root ganglion excitability. Related Articles | Metrics

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TREM-1 mediates interaction between substantia nigra microglia and peripheral neutrophils Tong Shen, Guiyun Cui, Hao Chen, Long Huang, Wei Song, Jie Zu, Wei Zhang, Chuanying Xu, Liguo Dong, Yongmei Zhang 2024, 19 (6):  1375-1384.  doi: 10.4103/1673-5374.385843 Abstract ( 187 )   PDF (5918KB) ( 126 )   Save Microglia-mediated neuroinflammation is considered a pathological feature of Parkinson’s disease. Triggering receptor expressed on myeloid cell-1 (TREM-1) can amplify the inherent immune response, and crucially, regulate inflammation. In this study, we found marked elevation of serum soluble TREM-1 in patients with Parkinson’s disease that positively correlated with Parkinson’s disease severity and dyskinesia. In a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease, we found that microglial TREM-1 expression also increased in the substantia nigra. Further, TREM-1 knockout alleviated dyskinesia in a mouse model of Parkinson’s disease and reduced dopaminergic neuronal injury. Meanwhile, TREM-1 knockout attenuated the neuroinflammatory response, dopaminergic neuronal injury, and neutrophil migration. Next, we established an in vitro 1-methyl-4-phenyl-pyridine-induced BV2 microglia model of Parkinson’s disease and treated the cells with the TREM-1 inhibitory peptide LP17. We found that LP17 treatment reduced apoptosis of dopaminergic neurons and neutrophil migration. Moreover, inhibition of neutrophil TREM-1 activation diminished dopaminergic neuronal apoptosis induced by lipopolysaccharide. TREM-1 can activate the downstream CARD9/NF-κB proinflammatory pathway via interaction with SYK. These findings suggest that TREM-1 may play a key role in mediating the damage to dopaminergic neurons in Parkinson’s disease by regulating the interaction between microglia and peripheral neutrophils. Related Articles | Metrics

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SARS-CoV2 Nsp3 protein triggers cell death and exacerbates amyloid β42-mediated neurodegeneration Aditi Singh, Anuradha Venkatakrishnan Chimata, Prajakta Deshpande, Soumya Bajpai, Anjali Sangeeth, Mrigendra Rajput, Amit Singh 2024, 19 (6):  1385-1392.  doi: 10.4103/1673-5374.382989 Abstract ( 79 )   PDF (5608KB) ( 86 )   Save Infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) virus, responsible for the coronavirus disease 2019 (COVID-19) pandemic, induces symptoms including increased inflammatory response, severe acute respiratory syndrome (SARS), cognitive dysfunction like brain fog, and cardiovascular defects. Long-term effects of SARS-CoV2 COVID-19 syndrome referred to as post-COVID-19 syndrome on age-related progressive neurodegenerative disorders such as Alzheimer’s disease remain understudied. Using the targeted misexpression of individual SARS-CoV2 proteins in the retinal neurons of the Drosophila melanogaster eye, we found that misexpression of nonstructural protein 3 (Nsp3), a papain-like protease, ablates the eye and generates dark necrotic spots. Targeted misexpression of Nsp3 in the eye triggers reactive oxygen species production and leads to apoptosis as shown by cell death reporters, terminal deoxynucleotidyl transferase (TdT) dUTP Nick-end labeling (TUNEL) assay, and dihydroethidium staining. Furthermore, Nsp3 misexpression activates both apoptosis and autophagy mechanism(s) to regulate tissue homeostasis. Transient expression of SARS-CoV2 Nsp3 in murine neuroblastoma, Neuro-2a cells, significantly reduced the metabolic activity of these cells and triggers cell death. Misexpression of SARS-CoV2 Nsp3 in an Alzheimer’s disease transgenic fly eye model (glass multiple repeats [GMR]>amyloid β42) further enhances the neurodegenerative rough eye phenotype due to increased cell death. These findings suggest that SARS-CoV2 utilizes Nsp3 protein to potentiate cell death response in a neurodegenerative disease background that has high pre-existing levels of neuroinflammation and cell death.  Related Articles | Metrics