Reactive Astrocyte Proliferation Research Articles

Trends and hotspots in acupuncture treatment of rat models of stroke: a bibliometric analysis from 2004 to 2023.

Acupuncture is a widely used clinical treatment method, and studies have confirmed its therapeutic effects on stroke patients. It can also reduce the burden on patients and society. Acupuncture treatment is a complementary and preventive treatment for stroke. However, there has yet to be a visual bibliometric analysis of the field of acupuncture for stroke rat models. This study explores future trends, research hotspots, and frontiers in acupuncture for stroke rat models over the past 20 years through investigation and visualization. We collected literature data on acupuncture treatment of stroke in rats from the Web of Science Core Collection (WOSCC) database from January 1, 2004, to December 31, 2023. Import into CiteSpace (version 6.2.R4) and RStudio for analysis by author, country/region, affiliation, annual publication, keywords, and journal visualization. A total of 379 articles were retrieved, including articles from 16 countries, 258 research institutions, and 123 academic journals. The countries and institutions with the most publications were the People's Republic of China (338) and the Fujian University of Traditional Chinese Medicine (43). Tao, Jing had the highest number of co-citations (144). The keywords and co-citation clustering show the main research directions in the field, including "artery occlusion," "neural regeneration," "stimulation," "rapid tolerance," "receptor," "signaling pathway," "apoptosis," "oxidative stress," "inflammatory response," "endogenous neurogenesis," "tolerance of local cerebral ischemic tissues," "proliferation of reactive astrocytes" and "neuroprotective effect." The intervention combines classical acupuncture treatment and modern technology (electricity) with electroacupuncture as a new intervention modality. This study demonstrates the increasing research on acupuncture for treating stroke in rat models. The country/region with the most publications is the People's Republic of China. However, international cooperation still needs to be improved, and future researchers must strengthen international cooperation. In addition, in future studies, researchers should improve the overall quality of research results in this area and enhance research protocols.

LNC000152 Mediates Aluminum-Induced Proliferation of Reactive Astrocytes.

Aluminum is a metal element with significant neurotoxicity, and there is a substantial correlation between aluminum exposure and cognitive dysfunction. Glial fibrillary acidic protein (GFAP) is widely used as a marker of reactive astrocyte proliferation in response to pathological injury of the central nervous system. Studies of various neurodegenerative diseases have confirmed that the expression changes in GFAP are associated with nerve injury. We investigated the role of LNC000152 in the aluminum-induced reactive proliferation of astrocytes. By establishing two aluminum-exposed cell models of rat primary astrocytes and CTX-TNA2 cell lines, we examined the expression of LNC000152 and GFAP and detected cell proliferation with EdU and cell cycle changes with flow cytometry. The role of aluminum in promoting glial cell proliferation was verified; the expression levels of LNC000152 and GFAP increased with the concentration of aluminum exposure. Intervention of LNC000152 expression by siRNA technology revealed that LNC000152 affected glial cell responsive proliferation by influencing GFAP expression. These results suggest that LNC000152 plays a role in the reactive proliferation of astrocytes induced by aluminum.

Effects of liraglutide on astrocyte polarization and neuroinflammation in db/db mice: focus on iron overload and oxidative stress.

Neuroinflammation plays a crucial role in the occurrence and development of cognitive impairment in type 2 diabetes mellitus (T2DM), but the specific injury mechanism is not fully understood. Astrocyte polarization has attracted new attention and has been shown to be directly and indirectly involved in neuroinflammation. Liraglutide has been shown to have beneficial effects on neurons and astrocytes. However, the specific protection mechanism still needs to be clarified. In this study, we assessed the levels of neuroinflammation and A1/A2-responsive astrocytes in the hippocampus of db/db mice and examined their relationships with iron overload and oxidative stress. First, in db/db mice, liraglutide alleviated the disturbance of glucose and lipid metabolism, increased the postsynaptic density, regulated the expression of NeuN and BDNF, and partially restored impaired cognitive function. Second, liraglutide upregulated the expression of S100A10 and downregulated the expression of GFAP and C3, and decreased the secretion of IL-1β, IL-18, and TNF-α, which may confirm that it regulates the proliferation of reactive astrocytes and A1/A2 phenotypes polarize and attenuate neuroinflammation. In addition, liraglutide reduced iron deposition in the hippocampus by reducing the expression of TfR1 and DMT1 and increasing the expression of FPN1; at the same time, liraglutide by up-regulating the levels of SOD, GSH, and SOD2 expression, as well as downregulation of MDA levels and NOX2 and NOX4 expression to reduce oxidative stress and lipid peroxidation. The above may attenuate A1 astrocyte activation. This study preliminarily explored the effect of liraglutide on the activation of different astrocyte phenotypes and neuroinflammation in the hippocampus of a T2DM model and further revealed its intervention effect on cognitive impairment in diabetes. Focusing on the pathological consequences of astrocytes may have important implications for the treatment of diabetic cognitive impairment.

131 Hedgehog Signaling Mediates Astrocytic Response and Blood-Brain Barrier Repair Following Traumatic Central Nervous System Injury

INTRODUCTION: Injury to the central nervous system (CNS) provokes a multicellular response to facilitate restoration of tissue homeostasis. Astrocytes consolidate at the lesion site to form a “glial scar” which restricts leukocyte infiltration and repairs the blood-brain barrier (BBB). However, this “scar” has been considered an impediment to regeneration and functional recovery. Therefore, uncovering molecular regulators that may be therapeutically targeted to promote pro-regenerative astrocyte phenotypes is of great interest. METHODS: Genetic reporter and conditional mutant mice were used to monitor, constitutively activate, or ablate Hh signaling following stereotactically-induced penetrating cortical or spinal cord injury. Outcomes including reactive astrocyte proliferation and polarization, leukocyte restriction, and blood-brain barrier repair were assessed via immunohistochemistry. RESULTS: Astrocytic expression of the Hh target gene Gli1 was downregulated acutely following injury but restored in the subacute phase. Constitutive activation of Hh signaling reduced astrocytic proliferation (%BrdU/EdU+ = 9.6% vs. 51.0%, p<0.01) and polarization (L/W Ratio = 2.8 vs. 1.5, p < 0.01). Additionally, in the spinal cord, constitutive activation impaired migration and integration of reactive astrocytes into the white matter lesion site. In animals with intact Hh signaling, the BBB recovered by 28 days after injury as evidenced by low levels of plasma protein and leukocyte infiltration. In contrast, conditional ablation of Hh signaling from 14-16 days after injury resulted in persistent BBB defects at 28 days. CONCLUSIONS: Our results suggest that acute downregulation of Hh signaling is required to specify reactive astrocyte properties including polarization and cell cycle re-entry. However, restoration of Hh signaling, which occurs subacutely from 10-28 days after injury and coincides with glial scar maturation, is required for leukocyte restriction and BBB repair. Understanding the temporospatial dynamics of postinjury Hh signaling is essential to modeling future therapeutic targets.

Specific knockout of Sox2 in astrocytes reduces reactive astrocyte formation and promotes recovery after early postnatal traumatic brain injury in mouse cortex.

In response to central nervous system (CNS) injury, astrocytes go through a series of alterations, referred to as reactive astrogliosis, ranging from changes in gene expression and cell hypertrophy to permanent astrocyte borders around stromal cell scars in CNS lesions. The mechanisms underlying injury-induced reactive astrocytes in the adult CNS have been extensively studied. However, little is known about injury-induced reactive astrocytes during early postnatal development. Astrocytes in the mouse cortex are mainly produced through local proliferation during the first 2 weeks after birth. Here we show that Sox2, a transcription factor critical for stem cells and brain development, is expressed in the early postnatal astrocytes and its expression level was increased in reactive astrocytes after traumatic brain injury (TBI) at postnatal day (P) 7 in the cortex. Using a tamoxifen-induced hGFAP-CreERT2; Sox2flox/flox ; Rosa-tdT mouse model, we found that specific knockout of Sox2 in astrocytes greatly inhibited the proliferation of reactive astrocytes, the formation of glia limitans borders and subsequently promoted the tissue recovery after postnatal TBI at P7 in the cortex. In addition, we found that injury-induced glia limitans borders were still formed at P2 in the wild-type mouse cortex, and knockout of Sox2 in astrocytes inhibited the reactivity of both astrocytes and microglia. Together, these findings provide evidence that Sox2 is essential for the reactivity of astrocytes in response to the cortical TBI during the early postnatal period and suggest that Sox2-dependent astrocyte reactivity is a potential target for therapeutic treatment after TBI.

The Efficacy of N-Acetyl-Cysteine (NAC) Supplementation in FST Model for Screening Antidepressants.

The model for screening antidepressant-like activity in pre-clinical drug studies include, rat forced swimming test (FST). The reports on N-acetylcysteine (NAC) as an antioxidant supplement in stress related disorder is well documented. This study was aimed at potential antidepressant mechanism of N-Acetyl Cysteine (NAC), a glutamate precursor on FST animal model for screening antidepressant drugs using fluoxetine, a selective serotonin reuptake inhibitors (SSRIs) as standard antidepressant drug. Thirty adult male Wistar rats used for this study were randomly divided into six groups each with five (n=5) rats. The control group (A) received 1 ml of normal saline daily, group B served as the FST model, group C received 200mg/kg/day of NAC, group D received 20mg/kg/day of fluoxetine, group E the FST model treated with 200mg/kg/day of NAC, and F is the FST model treated with 20mg/kg/day of fluoxetine. Drugs were given orally. The effects of NAC on brain weights, the FST paradigms, sucrose preference test (SPT) for anhedonia were assessed and data analyzed using ANOVA where Tukey post-hoc test for statistical significance was set at (p < 0.05). The brains fixed in 4% paraformaldehyde, were processed and the paraffin embedded tissue were serially sectioned at 5 μm thick to be stained using Haematoxylin and Eosin (H and E) stain, immuno-histochemistry for synaptophysin (p38) and astrocytes (GFAP) activities in the prefrontal cortex (PFC). Findings showed that NAC prevented FST-induced anxiety-like behaviors demonstrated by an increased SPT (that alleviates anhedonia), mobility time, and reduced immobility time. NAC caused an increase in brain weights and prevented FST-induced neurodegeneration, the proliferation of reactive astrocytes, and diminished synaptophysin immunoreactivity in the PFC similar to that seen in fluoxetine a standard anti-depressant drug. NAC treatment significantly exhibits its neuroprotective mechanism via inhibiting the proliferation of reactive astrocytes, which protects neurons and synapses from oxidative tissue damage induced by FST, hence an increase in synaptophysin activity that culminates in increased neural activity, increased SPT, and reduced immobility time.

N-acetylcysteine Alleviates Depression through Up-regulation of Synaptophysin, Inhibition of Reactivity Astrocytes, and Anhedonia in the Forced Swim Test Animal Model

Depression is a mental disorder of global concern, with chronic psychological stress being one of the underlying predisposing factors. This study evaluated the role of the antioxidant, N-acetylcysteine (NAC), as an antidepressant using the forced swim test (FST) animal model. Thirty adult male Wistar rats (250 g average weight) were randomly grouped into six (n=5): Control (1 ml/day of normal saline); FST model; NAC (200 mg/kg/day); Fluoxetine (20 mg/kg/day); FST model treated with NAC (200 mg/kg/day), and FST model treated with Fluoxetine (20 mg/kg/day). All the treatments were orally. The FST, sucrose-preference test (SPT), and brain weights were assessed, and data analysed. The histo-architecture of the prefrontal cortex (PFC), as well as the immunohistochemistry of astrocytes and synaptophysin were also assessed. Findings showed that NAC prevented FST-induced depressive behaviour demonstrated by increased SPT and mobility time. NAC also prevented the FST-induced decreased brain weights and neuronal loss, reduced proliferation of reactive astrocytes, and diminished synaptophysin immunoreactivity in the PFC similar to that of fluoxetine, a standard antidepressant drug. NAC exhibited its neuroprotective mechanism via inhibiting the proliferation of reactive astrocytes, and protecting neurons and synapses from oxidative tissue damage induced by FST, hence, an increase in synaptophysin activity that culminated in increased neural activity, increased SPT, and reduced immobility time.

Dynamic Evolution of the Glymphatic System at the Early Stages of Subarachnoid Hemorrhage.

The early stages of subarachnoid hemorrhage (SAH) are extremely important for the progression and prognosis of this disease. The glymphatic system (GS) has positive implications for the nervous system due to its ability to clearance tau and amyloid-β (Aβ) protein. Previous studies have shown that GS dysfunction will appear after SAH. However, there is no systematic evaluation of the degree of damage and development process of GS function in the early stage after SAH. In this study, we evaluated the GS function and neurobehavioral in the sham, 6 h, 1, 3, and 7 days after SAH, respectively. Our results showed that the function of GS was severely attenuated in mice after SAH with a decreased polarity of Aquaporin-4 (AQP4), increased expression of AQP4, a linear correlation with the dystrophin-associated complex (DAC), the proliferation of reactive astrocytes, increased tau protein accumulation, and decreased neurological function. Collectively, these findings provide a comprehensive understanding of the functional changes of GS after SAH, provide references for subsequent scholars studying SAH, and suggest some potential mechanistic insight that affects AQP4 polarity and GS function.

Alpha lipoic acid reverses scopolamine-induced spatial memory loss and pyramidal cell neurodegeneration in the prefrontal cortex of Wistar rats.

Neurodegenerative disorders are linked to oxidative tissue damage characterized by gradual loss of cognitive functions and neuronal cells. Alpha-lipoic acid (AHA) has a strong antioxidant property. Scopolamine is an anti-muscarinic agent used to study the mechanism of memory loss in an animal model. This study is aimed at evaluating the antioxidant role of alpha lipoic acid in reversing scopolamine induced memory loss and neurodegenerative process in the prefrontal cortex of Wistar rats. Twenty adult male Wistar rats used were divided into four groups (n = 5): Group 1 received vehicle (Control), Group 2 had scopolamine (1 mg/kg, i.p) for 4 days, Group 3 received AHA (200 mg/kg, p.o) for 10 days while Group 4 were pretreated with scopolamine (1 mg/kg, i.p) for 4 days followed by oral administration of 200 mg/kg of AHA for 10 days. The rats were subjected to Y-maze test to assess their spatial memory. The rats were euthanized, the prefrontal area was excised and fixed in 10% formol-calcium and processed for Haematoxylin and Eosin, Cresyl fast violet for Nissl Bodies (Ribosome), and Glial Fibrillary Acidic Protein (GFAP) stains. Scopolamine caused a significant decline in spatial working memory, prefrontal neuron cell loss, and increased proliferation of reactive astrocytes (astrogliosis) when compared with the control and AHA treated group. AHA process of reversing scopolamine-induced memory deficit, prefrontal neuron cell loss, and generation of reactive astrocytes (astrogliosis) is mediated by its antioxidant mediated positive modulation of astrocyte-neuronal interaction during neuroinflammation in response to oxidative tissue damage.

Valproic Acid Inhibits Glial Scar Formation after Ischemic Stroke

Introduction: Cerebral ischemia induces reactive proliferation of astrocytes (astrogliosis) and glial scar formation. As a physical and biochemical barrier, the glial scar not only hinders spontaneous axonal regeneration and neuronal repair but also deteriorates the neuroinflammation in the recovery phase of ischemic stroke. Objectives: Previous studies have shown the neuroprotective effects of the valproic acid (2-n-propylpentanoic acid, VPA) against ischemic stroke, but its effects on the ischemia-induced formation of astrogliosis and glial scar are still unknown. As targeting astrogliosis has become a therapeutic strategy for ischemic stroke, this study was designed to determine whether VPA can inhibit the ischemic stroke-induced glial scar formation and to explore its molecular mechanisms. Methods: Glial scar formation was induced by an ischemia-reperfusion (I/R) model in vivo and an oxygen and glucose deprivation (OGD)-reoxygenation (OGD/Re) model in vitro. Animals were treated with an intraperitoneal injection of VPA (250 mg/kg/day) for 28 days, and the ischemic stroke-related behaviors were assessed. Results: Four weeks of VPA treatment could markedly reduce the brain atrophy volume and improve the behavioral deficits in rats’ I/R injury model. The results showed that VPA administrated upon reperfusion or 1 day post-reperfusion could also decrease the expression of the glial scar makers such as glial fibrillary acidic protein, neurocan, and phosphacan in the peri-infarct region after I/R. Consistent with the in vivo data, VPA treatment showed a protective effect against OGD/Re-induced astrocytic cell death in the in vitro model and also decreased the expression of GFAP, neurocan, and phosphacan. Further studies revealed that VPA significantly upregulated the expression of acetylated histone 3, acetylated histone 4, and heat-shock protein 70.1B in the OGD/Re-induced glial scar formation model. Conclusion: VPA produces neuroprotective effects and inhibits the glial scar formation during the recovery period of ischemic stroke via inhibition of histone deacetylase and induction of Hsp70.1B.

Research progress of Notch signaling pathway in spinal cord injury

Spinal cord injury is a severe central nervous system disease, which will cause a series of complex pathophysiological changes and activate a variety of signaling pathways including Notch signaling. Studies have evidenced that activation of the Notch signaling pathway is not conducive to nerve repair and symptom improvement after spinal cord injury. Its mechanisms include inhibiting neuronal differentiation and axon regeneration, promoting reactive astrocyte proliferation, promoting M1 macrophage polarization and the release of proinflammatory factors, and inhibiting angiogenesis. Therefore, it has become a promising therapeutic strategy to inhibit Notch signal as a target in the treatment of spinal cord injury. In recent years, some researchers have used drugs, cell transplantation or genetic modification to regulate Notch signaling, which can promote the recovery of nerve function after spinal cord injury, thereby providing new treatment strategies for the treatment of spinal cord injury. This article will summarize the mechanism of Notch signaling pathway in spinal cord injury, and at the same time review the research progress in the treatment of spinal cord injury by modulating Notch signaling pathway in recent years, so as to provide new research ideas for further exploring new strategies for spinal cord injury.

Ski regulates proliferation and migration of reactive astrocytes induced by lipopolysaccharide (LPS) through PI3K/Akt pathway

Spinal cord injury (SCI) is a leading cause of disability and death worldwide. Reactive astrogliosis, a typical feature of SCI, undergoes various molecular and morphological changes and contributes to glial scar formation, which impedes axonal regeneration. Ski is a novel molecule that regulates the biological characteristics of astrocytes after spinal cord injury, but its function and the exact mechanism of its overexpression in reactive astrocyte proliferation and migration after SCI remain unclear. The purpose of this study was to elucidate the effect and mechanism of Ski on the proliferation and migration of reactive astrocytes, and to regulate the spatiotemporal formation of glial scars after SCI. In an in vitro lipopolysaccharide (LPS)-induced astrocyte injury model, the expression of Ski was upregulated in a time-dependent manner in LPS-induced astrocytes, and the upregulation of Ski was accompanied by that of PCNA, CDK4, CyclinD1, and other proliferation-related proteins. Our findings suggest that Ski promotes the proliferation and migration of reactive astrocytes. Next, astrocytes were transfected with a specific lentivirus to cause the overexpression of Ski, which significantly enhanced the proliferation and migration of reactive astrocytes and LPS-induced activation of the PI3K/Akt pathway. The PI3K/Akt pathway inhibitor LY294002 significantly inhibited the proliferation and migration of LPS-induced reactive astrocytes after Ski overexpression. In conclusion, Ski regulates LPS-induced astrocyte proliferation and migration through the PI3K/Akt pathway, making Ski a promising target for strategies to combat glial scarring after SCI.

The role of cell-free DNA in fibrinolysis for intraventricular hemorrhage.

Tissue plasminogen activator (tPA) fibrinolysis did not improve functional outcomes of patients with intraventricular hemorrhage (IVH), largely because of the unsatisfactory clot clearance. The presence of neutrophil extracellular traps (NETs) within the clot has been confirmed to impair tPA fibrinolysis, but the mechanism has been unclear. The authors hypothesized that cell-free DNA (cfDNA), the main framework of NETs, might be the important reason for the fibrinolysis resistance, and they validated the hypothesis, hoping to provide a new target to promote intraventricular fibrinolysis. First, cfDNA was detected in IVH clots by immunofluorescence staining in a rat model of IVH. Second, after blood (with or without exogenous cfDNA) intraventricular injection, IVH rats were given intraventricular infusion of 2 μl of saline, tPA, or tPA + DNase1 randomly. Then, the ventricular volume, animal behavior, and reactive astrocyte proliferation were assessed. Third, the IVH clots were collected for fibrinolysis assay in vitro. Finally, the effects of exogenous cfDNA in IVH were evaluated. The presence of cfDNA in clots was observed as early as 1 hour after IVH. Compared with the whole-blood model, blood + cfDNA caused more severe ventricular dilation (day 7: blood 32.47 ± 2.096 mm3 vs blood + DNA 40.09 ± 2.787 mm3, p < 0.05), increased fibrinolysis resistance to tPA (day 7: tPA + DNA 26.04 ± 1.318 mm3 vs tPA 22.15 ± 1.706 mm3, p < 0.05), and further deteriorated the functional defects in rats (blood vs blood + DNA, p < 0.05). Degradation of cfDNA by DNase1 further enhanced the fibrinolysis effects on relieving the ventricular dilation (day 7: tPA + DNase1 11.67 ± 2.023 mm3 vs tPA, p < 0.05), improving the functional outcome (tPA vs tPA + DNase1, p < 0.05) and reducing periventricular astrocyte proliferation. cfDNA impaired tPA fibrinolysis for IVH, and degradation of cfDNA may be a new target to improve this condition.

CSE-Derived H2S Inhibits Reactive Astrocytes Proliferation and Promotes Neural Functional Recovery after Cerebral Ischemia/Reperfusion Injury in Mice Via Inhibition of RhoA/ROCK2 Pathway.

The effect of cystathionine-γ-lyase (CSE)-derived hydrogen sulfide (H2S) on the reactive proliferation of astrocytes and neural functional recovery over 30 d after acute cerebral ischemia and reperfusion (I/R) was determined by applying wild-type (WT) and CSE knockout (KO) mice. The changes of glial fibrillary acidic protein (GFAP) expression in hippocampal tissues was tested. Besides, we assessed the changes of mice spatial learning memory ability, neuronal damage, RhoA, Rho kinase 2 (ROCK2), and myelin basic protein (MBP) expressions in hippocampal tissues. The results revealed that cerebral I/R resulted in obvious increase of GFAP expression in hippocampal tissues. Besides, we found the neuronal damage, learning, and memory deficits of mice induced by cerebral I/R as well as revealed the upregulation of RhoA and ROCK2 expressions and reduced MBP expression in hipppcampal tissues of mice following cerebral I/R. Not surprisingly, the GFAP expression and cerebral injury as well as the upregulation of the RhoA/ROCK2 pathway were more remarkable in CSE KO mice, compared with those in WT mice over 30 d following acute cerebral I/R, which could be blocked by NaHS treatment, a donor of exogenous H2S. In addition, the ROCK inhibitor Fasudil also inhibited the reactive proliferation of astrocytes and ameliorated the recovery of neuronal function over 30 d after cerebral I/R. For the purpose of further confirmation of the role of H2S on the astrocytes proliferation following cerebral I/R, the immunofluorescence double staining: bromodeoxyuridine (BrdU) and GFAP was evaluated. There was a marked upregulation of BrdU-labeled cells coexpressed with GFAP in hippocampal tissues at 30 d after acute cerebral I/R; however, the increment of astrocytes proliferation could be ameliorated by both NaHS and Fasudil. These findings indicated that CSE-derived H2S could inhibit the reactive proliferation of astrocytes and promote the recovery of mice neural functional deficits induced by a cerebral I/R injury via inhibition of the RhoA/ROCK2 signal pathway.

Alpha lipoic acid ameliorates scopolamine induced memory deficit and neurodegeneration in the cerebello-hippocampal cortex.

Scopolamine- induced memory loss is used to study new drug discovery in Alzheimer's disease (AD) pathogenesis. This study was aimed at evaluating the role of an antioxidant supplement alpha-lipoic acid (AHA), in ameliorating the oxidative damaging effects of scopolamine on cognition, memory, and the neurohistology of the cerebello-hippocampal cortex. Twenty adult male Wistar rats used were categorized into four (4) groups (n = 5): Group A- Control, Group B- 200mg/kg of AHA, Group C- Scopolamine (memory-impaired model), and Group D- Neurodegenerative repair model (Scopolamine + AHA). The treatment lasted for fourteen (14) days. Y-maze and hang-wire (limb use test) were used as behavioural index to assess memory and motor function while brain tissues were processed for histology (H and E stain), histochemistry using Cresyl Fast violet stain for Nissl bodies, and immunohistochemistry of astrocytes using glial fibrillary acidic protein (GFAP). Results showed that scopolamine led to a decline in brain weight, impaired memory and motor function, induced oxidative tissue damage cumulating in loss of neuronal cells, chromatolysis, the proliferation of reactive astrocytes (neuroinflammation biomarker) in the cerebello-hippocampal cortex; but upon administration of AHA these neuropathological characterizations were inhibited and reversed by AHA demonstrating its antioxidant and neuro- repair potential. In conclusion, AHA is a useful therapeutic agent against scopolamine-induced cognitive and memory deficit because it has the ability to ameliorate oxidative tissue damage by attenuating reactive astrocytes proliferation and neuron chromatolysis thereby improving memory and motor function.

TMAO Aggregates Neurological Damage Following Ischemic Stroke by Promoting Reactive Astrocytosis and Glial Scar Formation via the Smurf2/ALK5 Axis.

Ischemic stroke has been reported to cause significant changes to memory, thinking, and behavior. Intriguingly, recently reported studies have indicated the association of Trimethylamine N-oxide (TMAO) with the acute phase of ischemic stroke. However, the comprehensive underlying mechanism remained unknown. The objective of the present study was to investigate the association between TMAO and recovery of neurological function after ischemic stroke. For this purpose, a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model was established and treated with TMAO or/and sh-ALK5, followed by the neurological function evaluation. Behaviors of rats were observed through staircase and cylinder tests. Moreover, the expression of Smurf2 and ALK5 was detected by immunohistochemistry while expression of GFAP, Neurocan, and Phosphacan in brain tissues was determined by immunofluorescence. Thereafter, gain- and loss-of-function assays in astrocytes, the proliferation, viability, and migration were evaluated by the EdU, CCK-8, and Transwell assays. Besides, Smurf2 mRNA expression was determined by the RT-qPCR, whereas, Smurf2, ALK5, GFAP, Neurocan, and Phosphacan expression was evaluated by the Western blotting. Finally, the interaction of Smurf2 with ALK5 and ALK5 ubiquitination was assessed by the co-immunoprecipitation. Notably, our results showed that TMAO promoted the proliferation of reactive astrocyte and formation of glial scar in MCAO/R rats. However, this effect was abolished by the Smurf2 overexpression or ALK5 silencing. We further found that TMAO upregulated the ALK5 expression by inhibiting the ubiquitination role of Smurf2. Overexpression of ALK5 reversed the inhibitory effect of Smurf2 on astrocyte proliferation, migration, and viability. Collectively, our work identifies the evolutionarily TMAO/Smurf2/ALK5 signaling as a major genetic factor in the control of reactive astrocyte proliferation and glial scar formation in ischemic stroke, thus laying a theoretical foundation for the identification of ischemic stroke.

Biomaterials and strategies for repairing spinal cord lesions

Spinal cord injury (SCI) causes intractable disease and leads to inevitable physical, financial, and psychological burdens on patients and their families. SCI is commonly divided into primary and secondary injury. Primary injury occurs upon direct impact to the spinal cord, which leads to cell necrosis, axon disruption, and vascular loss. This triggers pathophysiological secondary injury, which has several phases: acute, subacute, intermediate, and chronic. These phases are dependent on post-injury time and pathophysiology and have various causes, such as the infiltration of inflammatory cells and release of cytokines that can act as a barrier to neural regeneration. Another unique feature of SCI is the glial scar produced from the reactive proliferation of astrocytes, which acts as a barrier to axonal regeneration. Interdisciplinary research is investigating the use of biomaterials and tissue-engineered fabrication to overcome SCI. In this review, we discuss representative biomaterials, including natural and synthetic polymers and nanomaterials. In addition, we describe several strategies to repair spinal cord injuries, such as fabrication and the delivery of therapeutic biocomponents. These biomaterials and strategies may offer beneficial information to enhance the repair of spinal cord lesions.

Salidroside Inhibits Reactive Astrogliosis and Glial Scar Formation in Late Cerebral Ischemia via the Akt/GSK-3β Pathway.

Cerebral ischemia leads to reactive astrogliosis and glial scar formation. Glial scarring can impede functional restoration during the recovery phase of stroke. Salidroside has been shown to have neuroprotective effects after ischemic stroke, but its impact on long-term neurological recovery, especially whether it regulates reactive astrogliosis and glial scar formation, is unclear. In this study, male adult C57/BL6 mice were subjected to transient cerebral ischemia injury followed by intravenous salidroside treatment. Primary astrocytes were treated with lipopolysaccharide (LPS) or conditioned medium from cultured primary neurons subjected to oxygen-glucose deprivation (CM-OGD). Salidroside significantly improved long-term functional outcomes following ischemic stroke in the rotarod and corner tests. It also reduced brain glial scar volume and decreased expression of the glial scar marker, glial fibrillary acidic protein (GFAP) and inhibited astrocyte proliferation. In primary astrocyte cultures, salidroside protected astrocytes from CM-OGD injury-induced reactive astroglial proliferation, increasing the percentage of cells in G0/G1 phase and reducing the S populations. The inhibitory effect of salidroside on the cell cycle was related to downregulation of cyclin D1 and cyclin-dependent kinase 4 (CDK4) mRNA expression and increased p27Kip1 mRNA expression. Similar results were found in the LPS-stimulated injury model in astroglial cultures. Western blot analysis demonstrated that salidroside attenuated the CM-OGD-induced upregulation of phosphorylated Akt and glycogen synthase kinase 3β (GSK-3β). Taken together, these results suggested that salidroside can inhibit reactive astrocyte proliferation, ameliorate glial scar formation and improve long-term recovery, probably through its effects on the Akt/GSK-3β pathway.

Effects of atorvastatin and aspirin on post-stroke epilepsy and usage of levetiracetam.

Objective:Atorvastatin and aspirin have been used in treating different forms of epilepsy. However, their effect on post-stroke epilepsy (PSE) still needs to be validated by large-scale clinical studies. In addition, their impact on the use of the antiepileptic drug levetiracetam for post-stroke epilepsy remains to be explored. Thus, the aim of this study was to further evaluate the effect of atorvastatin and aspirin on PSE and their effect on the usage of the antiepileptic drug levetiracetam in PSE patients.Methods:Patients, aged 65 to 85 years, with newly diagnosed post-ischemic stroke epilepsy from August 30, 2014 to August 30, 2018 were included in the study, with the exclusion of those with coexisting conditions.Results:Initially, 1321 patients were included, and 780 remained in the study at the 1-year follow-up. During the study, atorvastatin treatment with or without aspirin reduced the number of clinical epileptic episodes in PSE patients. It also reduced the dosage of levetiracetam and achieved better control of epilepsy compared to levetiracetam mono-treatment. Aspirin co-treatment with levetiracetam did not result in a significant improvement. However, the combination of aspirin with atorvastatin significantly reduced the number of seizures compared to atorvastatin treatment alone.Conclusion:Atorvastatin and aspirin co-treatment with levetiracetam can reduce epilepsy in PSE patients and reduce the dosage of levetiracetam required for effective control of PSE.

Fatty Acid Binding Protein 7 is Involved in the Proliferation of Reactive Astrocytes, but not in Cell Migration and Polarity

Reactive gliosis is a defense mechanism to minimize and repair the initial damage after CNS injuries that is characterized by increases in astrocytic reactivity and proliferation, with enhanced expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Fatty acid binding protein 7 (FABP7) is abundantly expressed in several types of glial cells, such as astrocytes and oligodendrocyte precursor cells, during brain development and FABP7-positive astrocytes have been shown to be significantly increased in the mouse cortex after a stab injury. However, the functional significance of FABP7 in gliosis remains unclear. In the present study, we examined the mechanism of FABP7-mediated regulation of gliosis using an in vitro scratch-injury model using primary cultured astrocytes. Western blotting showed that FABP7 expression was increased significantly in scratch wounded astrocytes at the edge of the injury compared with intact astrocytes. Through monitoring the occupancy of the injured area, FAB7-KO astrocytes showed a slower proliferation rate compared with WT astrocytes after 48 hr, which was confirmed by BrdU immunostaining. There were no differences in cell migration and polarity of reactive astrocytes between FABP-KO and WT. Conclusively, our data suggest that FABP7 is important in the proliferation of reactive astrocytes in the context of CNS injury.