Neuronal Injury In Rats Research Articles

GM1 Ameliorates Neuronal Injury in Rats after Cerebral Ischemia and Reperfusion: Potential Contribution of Effects on SPTBN1-mediated Signaling

Monosialoganglioside GM1 (GM1) has long been used as a therapeutic agent for neurological diseases in the clinical treatment of ischemic stroke. However, the mechanism underlying the neuroprotective function of GM1 is still obscure until now. In this study, we investigated the effects of GM1 in ischemia and reperfusion (I/R) brain injury models. Middle cerebral artery occlusion and reperfusion (MCAO/R) rats were treated with GM1 (60 mg·kg−1·d−1, tail vein injection) for 2 weeks. The results showed that GM1 substantially attenuated the MCAO/R-induced neurological dysfunction and inhibited the inflammatory responses and cell apoptosis in ischemic parietal cortex. We further revealed that GM1 inhibited the activation of NFκB/MAPK signaling pathway induced by MCAO/R injury. To explore its underlying mechanism of the neuroprotective effect, transcriptome sequencing was introduced to screen the differentially expressed genes (DEGs). By function enrichment and PPI network analyses, Sptbn1 was identified as a node gene in the network regulated by GM1 treatment. In the MCAO/R model of rats and oxygen-glucose deprivation and reperfusion (OGD/R) model of primary culture of rat cortical neurons, we first found that SPTBN1 was involved in the attenuation of I/R induced neuronal injury after GM1 administration. In SPTBN1-knockdown SH-SY5Y cells, the treatment with GM1 (20 μM) significantly increased SPTBN1 level. Moreover, OGD/R decreased SPTBN1 level in SPTBN1-overexpressed SH-SY5Y cells. These results indicated that GM1 might achieve its potent neuroprotective effects by regulating inflammatory response, cell apoptosis, and cytomembrane and cytoskeleton signals through SPTBN1. Therefore, SPTBN1 may be a potential target for the treatment of ischemic stroke.

Inhibition of phosphodiesterase 4 attenuates aquaporin 4 expression and astrocyte swelling following cerebral ischemia/reperfusion injury.

We have previously shown that phosphodiesterase 4 (PDE4) inhibition protects against neuronal injury in rats following middle cerebral artery occlusion/reperfusion (MCAO/R). However, the effects of PDE4 on brain edema and astrocyte swelling are unknown. In this study, we showed that inhibition of PDE4 by Roflumilast (Roflu) reduced brain edema and brain water content in rats subjected to MCAO/R. Roflu decreased the expression of aquaporin 4 (AQP4), while the levels of phosphorylated protein kinase B (Akt) and forkhead box O3a (FoxO3a) were increased. In addition, Roflu reduced cell volume and the expression of AQP4 in primary astrocytes undergoing oxygen and glucose deprivation/reoxygenation (OGD/R). Consistently, PDE4B knockdown showed similar effects as PDE4 inhibition; and PDE4B overexpression rescued the inhibitory role of PDE4B knockdown on AQP4 expression. We then found that the effects of Roflu on the expression of AQP4 and cell volume were blocked by the Akt inhibitor MK2206. Since neuroinflammation and astrocyte activation are the common events that are observed in stroke, we treated primary astrocytes with interleukin-1β (IL-1β). Astrocytes treated with IL-1β showed decreased AQP4 and phosphorylated Akt and FoxO3a. Roflu significantly reduced AQP4 expression, which was accompanied by increased phosphorylation of Akt and FoxO3a. Furthermore, overexpression of FoxO3a partly reversed the effect of Roflu on AQP4 expression. Our findings suggest that PDE4 inhibition limits ischemia-induced brain edema and astrocyte swelling via the Akt/FoxO3a/AQP4 pathway. PDE4 is a promising target for the intervention of brain edema after cerebral ischemia.

Involvement of CKS1B in the anti-inflammatory effects of cannabidiol in experimental stroke models

We have previously demonstrated that treatment with cannabidiol (CBD) ameliorates mitochondrial dysfunction and attenuates neuronal injury in rats following cerebral ischemia. However, the role of CBD in the progression of ischemic stroke-induced inflammation and the molecules involved remain unclear. Here, we found that CBD suppressed the production of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), reduced the activation of microglia, ameliorated mitochondrial deficits, and decreased the phosphorylation of nuclear factor κ-B (NF-κB) in BV-2 cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Cyclin-dependent kinase regulatory subunit 1B (CKS1B) expression was decreased in BV-2 cells following OGD/R and this reduction was blocked by treatment with CBD. Knockdown of CKS1B increased the activation of microglia and enhanced the production of IL-1β and TNF-α in BV-2 cells treated with CBD. Moreover, CKS1B knockdown exacerbated mitochondrial deficits and increased NF-κB phosphorylation. CBD treatment also ameliorated brain injury, reduced neuroinflammation, and enhanced the protein levels of mitochondrial transcription factor A and CKS1B in rats following middle cerebral artery occlusion/reperfusion. These data identify CKS1B as a novel regulator of neuroinflammation; and reveals its involvement in the anti-inflammatory effects of CBD. Interventions targeting CKS1B expression are potentially promising for treating in ischemic stroke.

Ocimum sanctum extract preserves neuronal echotexture and controls seizure in lithium-pilocarpine induced status epilepticus rats

Objective: To investigate the effect of Ocimum sanctum hydroalcoholic extract (OSHE) on seizure control and neuronal injury in rats with lithium-pilocarpine-induced status epilepticus (SE). Methods: SE was induced by administering lithium chloride followed by pilocarpine 24 h later. OSHE was administered either alone or in combination with valproate (VPA) 3 days before SE induction until 14 days post-SE induction. Seizure parameters were recorded on day 1 (0-3 h), day 1-3 and day 4-14 post-SE. On day 14 post-SE, neurobehavioural tests (elevated plus maze and passive avoidance) were done followed by total antioxidant capacity, neuron-specific enolase, immunohistochemistry, and electron microscopic assessment in the hippocampus and cortex tissue. Results: OSHE+VPA provided more significant seizure protection (75%) than VPA (62.5%), OSHE (62.5%), or SE control (12.5%) (overall P=0.003). The latency to stage-3/4 seizures was increased and the number of stage-3/4 seizures was reduced in all treatment groups compared to the SE control group (P=0.002 and <0.001, respectively). The OSHE+VPA group also had better memory retention than other treatment groups (P<0.001) in the passive avoidance test. Total antioxidant capacity level was significantly higher and neuron-specific enolase was lower in the OSHE and OSHE+VPA groups compared to the SE control group. Electron microscopic study showed significant myelin sheath damage (67.5%, P<0.05) and axonal degeneration (51.8%, P<0.001) in the hippocampus of the SE control group, which were alleviated by OSHE or OSHE+VPA treatment. In immunohistochemical analysis, the OSHE, OSHE+VPA, and VPA groups had a significantly higher number of viable neurons and less neuronal loss compared to the SE control in the hippocampus (P<0.001). Conclusions: OSHE either alone or in combination with VPA shows better seizure control by preservation of neuronal echotexture and reducing oxidative stress in the hippocampus.

Integrated Metabolomics and Network Pharmacology to Reveal the Mechanisms of Gandouling Tablets Against Copper-Overload-Induced Neuronal Injury in Rats with Wilson's Disease.

Gandouling Tablets (GDL), a proprietary Chinese medicine, have shown a preventive effect against Wilson's disease (WD)-induced neuronal damage in previous studies. However, the potential mechanisms need additional investigation. Combining metabonomics and network pharmacology revealed the GDL pathway against WD-induced neuronal damage. The WD rat model with a high copper load was developed, and nerve damage was assessed. Total metabonomics was used to identify distinct hippocampus metabolites and enriched metabolic pathways in MetaboAnalyst. The GDL's possible targets against WD neuron damage were then determined by network pharmacology. Cytoscape constructed compound metabonomics and pharmacology networks. Moreover, molecular docking and Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) validated key targets. GDL reduced WD-induced neuronal injury. Twenty-nine GDL-induced metabolites may protect against WD neuron injury. According to network pharmacology, we identified three essential gene clusters, of which genes in cluster 2 had the most significant impact on the metabolic pathway. A comprehensive investigation identified six crucial targets, including UGT1A1, CYP3A4, CYP2E1, CYP1A2, PIK3CB, and LPL, and their associated core metabolites and processes. Four targets reacted strongly with GDL active components. GDL therapy improved five targets' expression. This collaborative effort revealed the mechanisms of GDL against WD neuron damage and a way to investigate the potential pharmacological mechanisms of other Traditional Chinese Medicine (TCM).

The Protective Effect of Picroside II on Isoflurane-Induced Neuronal Injury in Rats via Downregulating miR-195

Introduction: Numerous pieces of evidence demonstrated that isoflurane induces hippocampal cell injury and cognitive impairments. Picroside II has been investigated for its anti-apoptosis and antioxidant neuroprotective effects. We aimed to explore the protective effects of picroside II and the role of microRNA-195 (miR-195) on isoflurane-induced neuronal injury in rats. Methods: The Morris water maze test was used to evaluate the effects of isoflurane on rats regarding escape latency and time in quadrant parameters. Real-time quantitative PCR was used to detect the expression levels of miR-195 and pro-inflammatory cytokines, including inter­leukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) mRNA, in the hippocampal tissues and neuronal cells. Results: The picroside II significantly improves isoflurane-induced higher escape latency and lower time spent in the quadrant compared with the control rats. Picroside II also promotes cell viability and suppresses cell apoptosis of isoflurane-induced neuronal cells. Besides, picroside II suppresses the expression of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and miR-195 in vivo and in vitro. Furthermore, overexpression of miR-195 abrogates the effects of picroside II on the expression of pro-inflammatory cytokines. The appropriate dose of picroside II is 20 mg/kg. Conclusion: Picroside II could protect the nervous system possibly through inhibiting the inflammatory response in the isoflurane-induced neuronal injury of rats. The protective effect of picroside II may be achieved by downregulating the expression of miR-195 and then inhibiting the inflammatory response.

Electroacupuncture Regulates Endoplasmic Reticulum Stress and Ameliorates Neuronal Injury in Rats with Acute Ischemic Stroke.

Ischemic stroke is a common cause of morbidity, mortality, and disability worldwide. Electroacupuncture (EA) is an effective method for alleviating brain damage after ischemic stroke. However, the underlying mechanism has not been fully elucidated. This study aimed to determine whether endoplasmic reticulum stress (ERS) could contribute to the protective effects of EA in cerebral ischemia/reperfusion injury (CIRI) to provide a rationale for the widespread clinical use of EA. Rats were divided into the sham-operated (sham) group, the CIRI (model) group, and the EA group. Rats in the model group were subjected to middle cerebral artery occlusion (MCAO) for 2 h followed by 72 h of reperfusion. Rats with CIRI were treated daily with EA at GV20 and ST36 for a total of 3 days. The Longa scoring system and adhesive removal somatosensory test were applied to evaluate neurological deficits. Then, 2,3,5-triphenyltetrazolium chloride (TTC) staining was performed to measure the infarct volume. Immunofluorescence staining for NeuN and GFAP and terminal deoxynucleotidyl transferase- (TdT-) mediated dUTP nick-end labeling (TUNEL) staining were performed to detect apoptotic cells in brain tissue. Immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR), and western blotting were used to measure the levels of ERS indicators (GRP78, CHOP/GADD153, p-eIF2α, and caspase 12). The results showed that EA significantly reduced the cerebral infarct volume, improved neurological function, and inhibited neuronal apoptosis. In the EA group compared with the model group, the mRNA expression levels of GRP78 were significantly increased, and the expression levels of proapoptotic proteins (CHOP/GADD153, p-eIF2α, and caspase 12) were significantly decreased. These results suggest that the possible mechanism by which EA protects cells against neuronal injury in CIRI may involve inhibiting endoplasmic reticulum stress.

Dexmedetomidine Inhibits Inflammation to Alleviate Early Neuronal Injury via TLR4/NF-κB Pathway in Rats with Traumatic Brain Injury.

Purpose - This study aims to explore the potential mechanism of dexmedetomidine in terms of inhibiting inflammation to alleviate early neuronal injury via TLR4/NF-κB pathway in rats with traumatic brain injury. Methods - The model of brain injury was established in rats. After the model was established, the rats were randomly divided into five groups: Sham, Sham + DEX, TBI, TBI + vehicle, and TBI + DEX. Each group included 10 rats. The water content in the brain tissue was measured. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assays were performed on histopathological tissue sections to evaluate neuronal apoptosis. Enzyme-linked immunosorbent assay and PCR were applied to detect the levels of the inflammatory factors, TNF-α, IL-1β, IL-6, and NF-κB. Results - TBI-challenged rats exhibited significant neuronal apoptosis, which was characterized via the wet-to-dry weight ratio, neurobehavioral functions, TUNEL assay results, and the levels of cleaved caspase-3, Bax upregulation, and Bcl-2, which were attenuated by DEX. Western blot, immunohistochemistry, and PCR results revealed that DEX promoted TLR4 expression and upregulated expression of the TLR4 downstream factors, HO-1 and NQO-1. Furthermore, DEX treatment markedly prevented the downregulation of inflammatory response factors, TNF-α, IL-1β and NF-κB, and IL-6. Conclusion - Dexmedetomidine is able to inhibit inflammation and attenuate early neuronal injury in rats with acute brain injury, which may act on TLR4/NF-κB pathway.

Desoxyrhapontigenin attenuates neuronal apoptosis in an isoflurane-induced neuronal injury model by modulating the TLR-4/cyclin B1/Sirt-1 pathway

This study investigated the protective effect of desoxyrhapontigenin (DOP) against isoflurane (ISF)-induced neuronal injury in rats. Neuronal injury was induced in pups by exposing them to 0.75% ISF on postnatal day 7 with 30% oxygen for 6 h. The pups were treated with DOP 10 mg/kg, i.p., for 21 days after ISF exposure. The protective effect of DOP was estimated by assessing cognitive function using the neurological score and the Morris water maze. Neuronal apoptosis was assessed in the hippocampus using the TUNEL assay, and protein expression of caspase-3, Bax, and Bcl-2 was measured by Western blotting. The levels of cytokines and oxidative stress parameters were assessed by ELISA. Western blotting and RT-PCR were performed to measure the expression of NF-kB, TLR-4, Sirt-1, and cyclin B1 protein in the brain. The cognitive function and neurological function scores were improved in the DOP group compared with the ISF group. Moreover, DOP treatment reduced the number of TUNEL-positive cells and the expression of caspase-3, Bax, and Bcl-2 protein in the brains of rats with neuronal injury. The levels of mediators of inflammation and oxidative stress were reduced in the brain tissue of the DOP group. Treatment with DOP attenuated the protein expression of TLR-4, NF-kB, cyclin B1, and Sirt-1 in the brain tissue of rats with neuronal injury. In conclusion, DOP ameliorates neuronal apoptosis and improves cognitive function in rats with ISF-induced neuronal injury. Moreover, DOP treatment can prevent neuronal injury by regulating the TLR-4/cyclin B1/Sirt-1 pathway.

Induction of BIS Protein During Astroglial and Fibrotic Scar Formation After Mitochondrial Toxin-Mediated Neuronal Injury in Rats.

B cell leukemia/lymphoma-2 (Bcl-2)-interacting death suppressor (BIS), also identified as Bcl-2-associated athanogene 3 (BAG3), has been reported to be upregulated in reactive astrocytes after brain insults. The present study was designed to further substantiate the involvement of BIS protein in the astroglial reaction in the striatum of rats treated with the mitochondrial toxin, 3-nitropropionic acid. Weak constitutive immunoreactivity for BIS was observed in astrocytes in the control striatum, whereas its expression was upregulated, along with that of nestin, in the lesioned striatum. In the lesion core, where astrocytes are virtually absent, BIS/nestin double-labeled cells were associated with the vasculature and were identified as perivascular adventitial fibroblasts. By contrast, BIS/nestin double-labeled cells in the perilesional area were reactive astrocytes, which were confined to the border zone contributing to the formation of the astroglial scar; this was evident 3days post-lesion and increased thereafter progressively throughout the 28-day experimental period. At the ultrastructural level, BIS protein was diffusely localized throughout the cytoplasm within the stained cells. Collectively, our results demonstrate the phenotypic and functional heterogeneity of BIS-positive cells in the lesioned striatum, suggesting the involvement of BIS in the formation of astroglial scar and its potential role in the development of fibrotic scar after brain insults.

Exogenous brain-derived neurotrophic factor attenuates neuronal apoptosis and neurological deficits after subarachnoid hemorrhage in rats.

Brain-derived neurotrophic factor (BDNF) is a growth factor crucial for neuronal survival, while its role in subarachnoid hemorrhage (SAH)-induced neuronal apoptosis remains unclear. The aim of the present study was to investigate whether administering exogenous BDNF can protect against neuronal apoptosis and neurological deficits following SAH in a rat model. The BDNF level was found to be significantly decreased in the basal cortex at 6, 12, 24, 48 and 72 h following SAH. Exogenous BDNF significantly decreased the expression of Bax and reduced activation of caspase-3 and caspase-9 and the number of apoptotic neurons. Moreover, exogenous BDNF treatment significantly improved the neurological deficits at 72 h and long-term behavioral deficits (day 14) following SAH in a rat model. These findings indicate that exogenous BDNF attenuated SAH-induced neuronal injury in rats.

Effect of miR-130a on neuronal injury in rats with intracranial hemorrhage through PTEN/PI3K/AKT signaling pathway.

The aim of this study was to investigate the effect of micro-ribonucleic acid (miR)-130a on neuronal injury in rats with intracerebral hemorrhage (ICH) through the phosphatase and tensin homolog deleted on chromosome ten/phosphatidylinositol 3-hydroxy kinase/protein kinase B (PTEN/PI3K/AKT) signaling pathway. A total of 30 healthy male rats were randomly divided into three groups, including the blank control group, ICH model group (ICH group) and ICH model + miR-130a treatment group (miR-130a treatment group). The differences in neurological injury, the number of apoptotic cells in brain tissues, the activity of Caspase-9 and protein expressions of PTEN/PI3K/AKT were analyzed among the three groups, respectively. Neurological function was normal without injury in the control group. However, the neurological injury was severe in the ICH group and mild in the miR-130a treatment group. There were statistically significant differences in neurological function in the control group relative to those of the ICH group and miR-130a treatment group (p<0.05). Meanwhile, the neurological injury was markedly milder in the miR-130a treatment group than that of the ICH group, showing a statistically significant difference (p<0.05). The number of apoptotic cells was remarkably smaller in the control group when compared with the ICH group and miR-130a treatment group. However, it was markedly larger in the ICH group than that of the miR-130a treatment group, showing significant differences (p<0.05). The activity of Caspase-9 was significantly lower in the control group than ICH group and miR-130a treatment group (p<0.05). However, it increased remarkably in the ICH group compared with that of the miR-130a treatment group (p<0.05). Moreover, the protein level of PTEN in the ICH group was significantly higher than control group and miR-130a treatment group, displaying statistically significant differences (p<0.05). However, no marked difference in the protein level of PTEN was observed between the control group and miR-130a treatment group (p>0.05). The protein levels of the phosphorylated 3-hydroxy kinase (p-PI3K) and phosphorylated protein kinase B (p-AKT) were remarkably lower in the ICH group than those of the control group and miR-130a treatment group, displaying statistically significant differences (p<0.05). However, they were remarkably higher in the miR-130a treatment group than that of the control group (p<0.05). MiR-130a promotes neuronal growth in brain tissues in ICH rats and alleviates neuronal injury after ICH through the PTEN/PI3K/AKT signaling pathway. Our findings suggest that miR-130a exerts important clinical significance in the treatment of ICH.

Endoplasmic Reticulum Stress Is Involved in Stress-Induced Hypothalamic Neuronal Injury in Rats via the PERK-ATF4-CHOP and IRE1-ASK1-JNK Pathways.

ObjectiveAs a high-level nerve center that regulates visceral and endocrine activity, the hypothalamus plays an important role in regulating the body’s stress response. Previous studies have shown that stress can cause damage to hypothalamic neurons. The present study aimed to further clarify the mechanism of endoplasmic reticulum stress (ERS) involvement in hypothalamic neuronal injury.MethodsA 7-day stressed rat model was established with daily restraining for 8 h and forced ice-water swimming for 5 min. The rats were randomly divided into control, stress, stress + GSK2606414 (PERK phosphorylation inhibitor), stress + KIRA6 (IRE1 phosphokinase activity inhibitor), GSK2606414, and KIRA6 groups. The pathological changes of hypothalamic neurons were observed by thionine staining. Expression of ERS proteins GRP78, ATF4, ASK1, JNK, and CHOP in the hypothalamic neurons were observed by immunohistochemical staining. The expression of JNK and CHOP mRNA in the hypothalamic neurons were observed by RNA in situ hybridization (RNA Scope) and the expression of related proteins and mRNA was semiquantitatively analyzed by microscopy-based multicolor tissue cytometry (MMTC).ResultsThionine staining revealed that stress exposure resulted in edema, a lack of Nissl bodies, and pyknosis in hypothalamic neurons. Immunohistochemistry and RNA Scope showed that stress exposure significantly increased the expression of GRP78, ATF4, ASK1, CHOP, JNK, JNK mRNA, and CHOP mRNA. Treatment with PERK and IRE1 inhibitors attenuated pathological damage and downregulated the expression of ATF4, ASK1, JNK, CHOP, JNK mRNA, and CHOP mRNA.ConclusionStress caused pathological changes in rat hypothalamic neurons. ERS PERK-ATF4-CHOP and IRE1-ASK1-JNK pathways were involved in the injury process.

Inactivation of P2YR12 contributes to isoflurane-induced neuronal injury by altering TLR-4/BDNF/TNF-α.

The present investigation evaluated the effect of inhibiting the P2Y12 gene on anaesthetic-induced neuronal injury in a rat model. Neuronal injury was induced by exposing the animals for 6 h to 30% oxygen containing 0.75% isoflurane and 1.2 mg/kg prasugrel (a P2Y12 inhibitor) p.o. for 14 days. Cognitive function was determined by the Morris water maze, and the neurological severity score was determined. Enzyme-linked immunosorbent assay was used to estimate the level of oxidative stress and mediators of inflammation in brain tissues of isoflurane-induced neuronal injury rats. Apoptosis of neuronal cells was estimated by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and western blot assays. Real time-polymerase chain reaction was performed to estimate the expression levels of several proteins. The data revealed that inhibiting the P2Y12 gene ameliorated changes in the modified neurological severity score and cognitive function in neuronal injury rats. Moreover the levels of proinflammatory mediators, oxidative stress, and cyclic AMP, and the number of TUNEL-positive cells, decreased significantly (p < 0.01) in the prasugrel-treated group compared to the negative control group. In addition, apoptosis of neuronal cells decreased in the prasugrel-treated group, as it ameliorated expression of the PI3K, Bcl-2, Bad, and Akt proteins in the isoflurane-induced neuronal injury rats. Expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) proteins was enhanced, whereas the Toll-like receptor-4 (TLR-4) and nuclear factor κB (NF-κB) proteins decreased in the brain tissues of the prasugrel-treated group compared to the negative control group of rats. These results suggest that inhibiting the P2YR12 gene protects against neuronal injury in isoflurane-induced neuronal injury rats. Inhibiting the P2YR12 gene ameliorated neuronal apoptosis by regulating the BDNF/TLR-4/TNF-α pathway.

Effects of agmatine on chlorpromazine-induced neuronal injury in rat

This study was aimed to study the potentially beneficial effects of agmatine on oxidative/nitrosative stress development in the brain of Wistar rats during subacute chlorpromazine treatment. The animals were divided into control (0.9% saline), chlorpromazine (38.7 mg/kg b.w.), chlorpromazine+agmatine (agmatine 75 mg/kg b.w. immediately after chlorpromazine, 38.7 mg/kg b.w. i.p.) and agmatine (75 mg/kg b.w.) groups. All the tested substances were administered intraperitoneally for 15 consecutive days and the rats were sacrificed by decapitation on day 15. Subacute administration of chlorpromazine resulted in increased lipid peroxidation, nitric oxide concentration and superoxide anion production, while completely damaging the antioxidant defence system in the cerebral cortex, striatum, and hippocampus. However, the combined treatment with chlorpromazine and agmatine significantly attenuated the oxidative/nitrosative stress indices and restored the antioxidant capacity to the control values in all of the examined brain regions. Western blot analysis supported biochemical findings in all groups, but the most notable changes were found in the hippocampus. Our results suggest potentially beneficial effects of agmatine, which may be useful in the modified antioxidant approach in chlorpromazine-therapy.

Effects of andrographolide on postoperative cognitive dysfunction and the association with NF-κB/MAPK pathway.

The present study investigated the effects of andrographolide on postoperative cognitive dysfunction (POCD) in aged rats to gain insight of the underlying mechanism, which may provide theoretical basis for the clinical application of andrographolide to prevent POCD in older patients. Thirty aged male rats were randomly assigned to 3 groups: Control, model and andrographolide groups. The Morris water maze test was used to examine the spatial memory and learning ability of the rats postoperatively. The histological alterations of neuronal cells in the hippocampus were visualized by H&E staining. The serum levels of neuron-specific enolase (NSE), human soluble protein-100β (S-100β) and the inflammation factors of interluekin (IL)-1β, IL-6 and TNF-α involved in the nuclear factor κB (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathway were detected by ELISA. The NF-κB/MAPK signaling pathway-associated proteins in rat serum were detected by western blotting. Following andrographolide treatment, the rats significantly gained learning ability after surgery. Is it ameliorated hippocampal neuronal injury in rats following surgery. Andrographolide decreased NSE, S-100β, and the inflammation factors, IL-6, IL-1β and TNF-α in serum. Andrographolide reduced NF-κB/MAPK pathway-associated protein expression. Andrographolide ameliorated POCD in aged rats following surgery. The underlying mechanism may be associated with the downregulation the inflammatory factors and NF-κB/MAPK-associated protein expression.

Schisantherin A attenuates ischemia/reperfusion-induced neuronal injury in rats via regulation of TLR4 and C5aR1 signaling pathways

Toll-like receptor 4 (TLR4) and C5aR1 (CD88) have been recognized as potential therapeutic targets for the reduction of inflammation and secondary damage and improvement of outcome after ischemia and reperfusion (I/R). The inflammatory responses which induce cell apoptosis and necrosis after I/R brain injury lead to a limited process of neural repair. To further comprehend how these targets function in I/R state, we investigated the pathological changes and TLR4 and C5aR1 signaling pathways in vitro and in vivo models of I/R brain injury in this study. Meanwhile, we explored the roles of schisantherin A on I/R brain injury, and whether it exerted neuroprotective effects by regulating the TLR4 and C5aR1 signaling pathways or not. The results showed that schisantherin A significantly reduced the neuronal apoptosis induced by oxygen and glucose deprivation and reperfusion (OGD/R) injury in primary culture of rat cortical neurons. Also, schisantherin A alleviated neurological deficits, reduced infarct volume, attenuated oxidation stress, inflammation and apoptosis in ischemic parietal cortex of rats after middle cerebral artery occlusion and reperfusion (MCAO/R) injury. Moreover, the activated TLR4 and C5aR1 signaling pathways were inhibited by schisantherin A treatment. In conclusion, TLR4 and C5aR1 played a vital role during I/R brain injury in rats, and schisantherin A exhibited neuroprotective effects by TLR4 and C5aR1 signaling pathways. These findings also provided new insights that would aid in elucidating the effect of schisantherin A against cerebral I/R and support the development of schisantherin A as a potential treatment for ischemic stroke.

Scutellaria barbata flavonoids alleviate memory deficits and neuronal injuries induced by composited Aβ in rats.

BackgroundThe aim of the present study was to investigate the effects of Scutellaria barbata flavonoids (SBF) on memory impairment and neuronal injury induced by amyloid beta protein 25–35 in combination with aluminum trichloride (AlCl3) and recombinant human transforming growth factor-β1 (RHTGF-β1) (composited Aβ) in rats.MethodsThe composited Aβ-treated model of Alzheimer’s disease (AD)-like memory impairment and neuronal injury was established in male rats by right intracerebroventricular injection of composited Aβ, and the effects of SBF were assessed using this rat model. Spatial learning and memory of rats were assessed in the Morris water maze, and neuronal injury was assessed by light and electron microscopy with hematoxylin-eosin or uranyl acetate and lead nitrate-sodium citrate staining, respectively.ResultsIn the Morris water maze, memory impairment was observed in 94.7% of the composited Aβ-treated rats. The composited Aβ-treated rats took longer than sham-operated rats to find the hidden platform during position navigation and reversal learning trials. They also spent less time swimming in the target quadrant in the probe trial. Optical and electron microscopic observations showed significant neuropathological changes including neuron loss or pyknosis in hippocampus, typical colliquative necrosis in cerebral cortex, mitochondrial swelling and cristae fragmentation and a large number of lipofuscin deposits in the cytoplasm. Treatment with SBF (35–140 mg/kg) reduced the memory impairment and neuronal injury induced by composited Aβ.ConclusionSBF-mediated improvement of composited Aβ-induced memory impairment and neuronal injury in rats provides an appropriate rationale for evaluating SBF as a promising agent for treatment of AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12993-016-0118-8) contains supplementary material, which is available to authorized users.

Pyruvate treatment attenuates cerebral metabolic depression and neuronal loss after experimental traumatic brain injury

Experimental traumatic brain injury (TBI) is known to produce an acute increase in cerebral glucose utilization, followed rapidly by a generalized cerebral metabolic depression. The current studies determined effects of single or multiple treatments with sodium pyruvate (SP; 1000mg/kg, i.p.) or ethyl pyruvate (EP; 40mg/kg, i.p.) on cerebral glucose metabolism and neuronal injury in rats with unilateral controlled cortical impact (CCI) injury. In Experiment 1 a single treatment was given immediately after CCI. SP significantly improved glucose metabolism in 3 of 13 brain regions while EP improved metabolism in 7 regions compared to saline-treated controls at 24h post-injury. Both SP and EP produced equivalent and significant reductions in dead/dying neurons in cortex and hippocampus at 24h post-CCI. In Experiment 2 SP or EP were administered immediately (time 0) and at 1, 3 and 6h post-CCI. Multiple SP treatments also significantly attenuated TBI-induced reductions in cerebral glucose metabolism (in 4 brain regions) 24h post-CCI, as did multiple injections of EP (in 4 regions). The four pyruvate treatments produced significant neuroprotection in cortex and hippocampus 1day after CCI, similar to that found with a single SP or EP treatment. Thus, early administration of pyruvate compounds enhanced cerebral glucose metabolism and neuronal survival, with 40mg/kg of EP being as effective as 1000mg/kg of SP, and multiple treatments within 6h of injury did not improve upon outcomes seen following a single treatment.

Glial cell-expressed mechanosensitive channel TRPV4 mediates infrasound-induced neuronal impairment

Vibroacoustic disease, a progressive and systemic disease, mainly involving the central nervous system, is caused by excessive exposure to low-frequency but high-intensity noise generated by various heavy transportations and machineries. Infrasound is a type of low-frequency noise. Our previous studies demonstrated that infrasound at a certain intensity caused neuronal injury in rats but the underlying mechanism(s) is still largely unknown. Here, we showed that glial cell-expressed TRPV4, a Ca(2+)-permeable mechanosensitive channel, mediated infrasound-induced neuronal injury. Among different frequencies and intensities, infrasound at 16Hz and 130dB impaired rat learning and memory abilities most severely after 7-14days exposure, a time during which a prominent loss of hippocampal CA1 neurons was evident. Infrasound also induced significant astrocytic and microglial activation in hippocampal regions following 1- to 7-day exposure, prior to neuronal apoptosis. Moreover, pharmacological inhibition of glial activation in vivo protected against neuronal apoptosis. In vitro, activated glial cell-released proinflammatory cytokines IL-1β and TNF-α were found to be key factors for this neuronal apoptosis. Importantly, infrasound induced an increase in the expression level of TRPV4 both in vivo and in vitro. Knockdown of TRPV4 expression by siRNA or pharmacological inhibition of TRPV4 in cultured glial cells decreased the levels of IL-1β and TNF-α, attenuated neuronal apoptosis, and reduced TRPV4-mediated Ca(2+) influx and NF-κB nuclear translocation. Finally, using various antagonists we revealed that calmodulin and protein kinase C signaling pathways were involved in TRPV4-triggered NF-κB activation. Thus, our results provide the first evidence that glial cell-expressed TRPV4 is a potential key factor responsible for infrasound-induced neuronal impairment.