Neuroprotective Effects In Rats Research Articles

BL-918 alleviates oxidative stress in rats after subarachnoid hemorrhage by promoting mitophagy through the ULK1/PINK1/Parkin pathway

Background and purposeOxidative stress plays a critical role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). The small molecule ULK1 agonist, BL-918, demonstrated neuroprotective effects in other central nervous system diseases; however, its role in SAH has not yet been explored. This study aimed to evaluate whether BL-918 could provide neuroprotective effects in rats following SAH. MethodsAn SAH model was established in Sprague-Dawley rats using endovascular perforation. BL-918 was administered intraperitoneally after SAH, while the ULK1 inhibitor SBI was given intraperitoneally prior to SAH modeling. PINK1 siRNA was administered into the lateral ventricle before SAH induction. The neuroprotective effects and mechanisms of BL-918 were assessed through SAH grading, brain water content measurement, blood-brain barrier permeability, neurobehavioral tests, Western blot, immunofluorescence, TUNEL staining, DHE staining, and transmission electron microscopy (TEM). ResultsAfter SAH, the expression levels of p-ULK1, PINK1, Parkin, and LC3Ⅱ increased, peaking at 24 h post-SAH. BL-918 treatment improved neurological function in rats, reduced brain water content and blood-brain barrier permeability, and exhibited anti-oxidative stress and anti-apoptotic effects. Western blot analysis revealed that BL-918 increased the expression of p-ULK1, PINK1, Parkin, LC3Ⅱ, Bcl-xl, and Bcl-2 while inhibiting the expression of Bax and Cleaved Caspase-3. Oxidative stress-related indicators showed that BL-918 alleviated oxidative stress. Immunofluorescence and TEM results demonstrated that BL-918 promoted mitophagy and preserved mitochondrial morphology. Furthermore, the positive effects of BL-918 were reversed by SBI and PINK1 siRNA, respectively. ConclusionBL-918 improved both short-term and long-term neurological impairments in rats after SAH and reduced oxidative stress by promoting mitophagy, at least partially through the ULK1/PINK1/Parkin signaling pathway.

Electroacupuncture protects against cerebral ischemia-reperfusion injury through mitochondrial dynamics

BackgroundElectroacupuncture (EA) has been shown to promote functional recovery after cerebral ischemia–reperfusion (I/R) injury. However, the contribution of mitochondrial dynamics to recovery remains unclear. The aim of this study was to investigate whether mitochondrial dynamics are involved in the effects of EA on cerebral I/R injury. MethodsThe rats with cerebral I/R injury were established by the middle cerebral artery occlusion/reperfusion. Subsequently, EA was applied to Baihui (GV20) and Dazhui (GV14) acupoints, with 2 Hz/5 Hz in frequency, 1.0 mA in intensity, 20 min each time, once a day for seven consecutive days. The therapeutic outcomes were assessed by modified neurological severity score (mNSS), 2,3,5-Triphenyte-trazolium chloride (TTC) staining, and hematoxylin-eosin (HE) staining. Mitochondrial morphology was observed under transmission electron microscopy. Adenosine triphosphate (ATP) content and ATP synthases (ATPases) activity were evaluated to measure mitochondrial function using ELISA. Finally, mitochondrial dynamics-related molecules, including dynamin-related protein 1 (Drp1), fission 1 (Fis1), mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), and optic atrophy 1 (OPA1), were detected by Western blot and immunofluorescence staining. ResultsCerebral I/R injury induced neurological dysfunction, cerebral infarction and neuronal injury, all of which were ameliorated by EA. And EA improved mitochondrial morphology and function. Moreover, EA altered the balance of mitochondrial dynamics. Specifically, the data showed a significant decrease in the expression of Drp1 and Fis1, leading to the inhibition of mitochondrial fission. Additionally, Mfn1, Mfn2 and Opa1, which are related to mitochondrial fusion, were effectively promoted after EA treatment. However, sham EA did not show any neuroprotective effects in rats with cerebral I/R injury. ConclusionsIn summary, our study indicates that the balance of mitochondrial dynamics is crucial for EA therapy to treat cerebral I/R injury.

Sodium butyrate exerts a neuroprotective effect in rats with acute carbon monoxide poisoning by activating autophagy through the mTOR signaling pathway

Acute carbon monoxide (CO) poisoning is a prevalent type of poisoning that causes significant harm globally. Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is a severe complication that occurs after acute CO poisoning; however, the exact underlying pathological cause of DEACMP remains unclear. Accumulating evidence indicates that abnormal inflammation and immune-mediated brain damage, cellular apoptosis and autophagy, and direct neuronal toxicity are involved in the development of delayed neurologic sequelae. Sodium butyrate, a histone deacetylase inhibitor, has gained increasing attention for its numerous beneficial effects on various diseases, such as obesity, diabetes, inflammatory diseases, and cerebral damage. In this study, an acute carbon monoxide poisoning (ACOP) model is established in rats to investigate the mechanism of CO poisoning and the therapeutic potential of sodium butyrate. The results suggested that the ACOP rats had impaired spatial memory, and cell apoptosis was observed in the hippocampi with activated autophagy. Sodium butyrate treatment further increased the activation of autophagy in the hippocampi of CO-exposed rats, inhibited apoptosis, and consolidated spatial memory. These findings indicated that sodium butyrate may improve memory and cognitive function in ACMP rats by promoting autophagy and inhibiting apoptosis.

Perindopril Possesses a Protective Impact on Neuronal Function by Lowering Inflammation and Oxidative Stress in Adult Male Rats During Ischemia/Reperfusion

Background: Cerebral ischemia/reperfusion (CI/R) is a separate feature of ischemic stroke that occurs when blood perfusion is restored following a period of ischemia. Despite the beneficial effects of reperfusion, it can cause even more harmful outcomes than persistent ischemia. Objectives: This study was conducted to assess perindopril's neuroprotective ability in (CI/R) and to conceptualize its molecular underpinnings. Materials and Methods: The 28 Sprague-Dawley male rats weighing 200-300 g were randomly divided into four groups, each with seven rats: Sham (undergo general anesthesia without bilateral common carotid artery occlusion (BCCO)), Control (30 min. of BCCO followed by reperfusion 60 minutes), Vehicle (7 days of distilled water then as control group), and Perindopril-treated group (7 days of Perindopril-treated then as control group). After reperfusion, the brain's tissues were extracted in order to evaluate the levels of biochemical, and total antioxidant capacity in addition to the extent of the infarct and histological investigation. Results: Cerebral infarct size, as well as levels of inflammatory marker were significantly higher in the control and vehicle groups compared to the sham groups, although overall anti-oxidant capability was significantly lower. Perindopril therapy increased IL-10 and overall antioxidant capacity while decreasing IL-6, TNF-\(\alpha\), NF-kB p65, and ICAM-1 significantly. Histopathological, both control and vehicle rats had severe ischemia damage, which was significantly alleviated by perindopril therapy. Conclusions: The perindopril neuroprotective effect in rats exposed to cerebral ischemia/reperfusion injury may be attributed to the anti-inflammatory and anti-oxidative effect of perindopril.

Administration of mitochondrial fusion promoter during ischemia and at the onset of reperfusion exert neuroprotective effects in rats with cardiac ischemia/reperfusion injury

AbstractBackgroundAcute myocardial infarction (AMI) is one of the fetal cardiovascular diseases and a leading cause of death (1, 2). Our previous study demonstrated that pretreatment of mitochondrial fusion promoter (M1) provided neuroprotective effects on the brain following cardiac ischemia/reperfusion (I/R) injury (3). However, the effects of M1 given during ischemia and M1 given at the onset of reperfusion on brain pathologies following cardiac I/R have never been investigated.MethodSixteen male Wistar rats were randomly divided into either a sham‐operation (n = 8) or cardiac I/R (n = 24). In the cardiac I/R group, rats were then randomly divided into 3 subgroups, including the I/R operation with vehicle (0.9% sodium chloride solution for 15 minutes before I/R protocol, intravenous (i.v.) injection), the I/R operation with M1 administration during cardiac ischemia (2 mg/kg, 15 minutes after left anterior descending (LAD) coronary artery ligation, i.v. injection), and the I/R operation with M1 administration at the onset of reperfusion group (2 mg/kg at the beginning of reperfusion, i.v. injection). At the end of experimental protocol, rats were sacrificed and brains were obtained for further molecular investigation.ResultThe results demonstrated that cardiac I/R increased brain inflammation, caused microglial dysmorphology, caused brain mitochondrial dysfunction, increased tau hyperphosphorylation, and increased brain apoptosis (p<0.05, Figure 1). M1 given during ischemia and M1 given at the onset of reperfusion effectively attenuated brain pathologies following cardiac I/R by preserving microglial morphology, improving brain mitochondrial function, decreasing tau hyperphosphorylation, and decreasing brain apoptosis (p<0.05, Figure 1). Interestingly, M1 given during ischemia had better efficacy to suppressing brain inflammation, when compared to M1 given at the onset of reperfusion apoptosis (p<0.05, Figure 1).ConclusionThese findings suggest the administration of mitochondrial fusion promoter effectively decreased brain pathologies following cardiac I/R. The administration of mitochondrial fusion promoter during ischemia had greater suppression on brain inflammation than administration at the onset of reperfusion. The novel findings obtained from the present study provided the therapeutic strategies which can be translated into clinical settings for cardiac I/R injury.

Muscle activity and emotional behavior changes in rats with chronic brain ischemia via comprehensive pathogenetic correction

Cerebrovascular pathology has evolved from a medical concern to a social issue, with the efficacy of secondary neuroprotection remaining a pertinent question. While some investigations have been conducted to elucidate the effectiveness of a comprehensively grounded pharmacological correction scheme under conditions of experimentaly induced chronic brain ischemia, further refinement is necessary to understand the behavioral effects of animals, dosages, routes of administration of pharmacological agents, and analysis of obtained data. The aim of this study was to assess the effectiveness of applying Semax and hopantenic acid in the comprehensive treatment of motor disorders and established neurological impairments in rats with experimentally induced chronic brain ischemia. We determined that rats with chronic brain ischemia exhibit muscular dysfunctions and experience pronounced disturbances in emotional behavior from the first day. It has been demonstrated that the separate and combined application of Semax and hopantenic acid contributes to the restoration of muscle activity, normalization of coordination, and emotional behavior in rats with chronic brain ischemia. The most significant neuroprotective effect in rats with chronic brain ischemia was observed with the combined administration of Semax and hopantenic acid, starting from the 3rd day of the trial. The subsequent in the series of anti-ischemic effectiveness is the impact of Semax from the 3rd day of the experiment. The least pronounced neuroprotective effect was exhibited by hopantenic acid, starting from the 5th day of the experiment. We consider these findings to be an experimental foundation supporting the feasibility of clinically testing the effects of combined Semax and hopantenic acid administration, capable of restoring functional disorders caused by chronic brain ischemia. In conclusion, the observed effectiveness of the developed pathogenetically justified complex for the correction of post-ischemic muscle dysfunction and disorders indicates the development of an anti-ischemic effect, as well as the fundamental possibility of improving the treatment for patients with chronic brain ischemia through clinical intranasal administration of Semax, either alone or in combination with hopantenic acid. However, for a more comprehensive understanding of the temporal and dose-dependent effects of this complex pathogenetic correction scheme on other disorders and dysfunctions related to chronic brain ischemia and to formulate final conclusions, it is essential to conduct separate series of experimental studies.

Neuroprotective effects of nobiletin on cerebral ischemia/reperfusion injury rats by inhibiting Rho/ROCK signaling pathway.

Nobiletin (NOB), an active natural flavonoid component of citrus, is used in Traditional Chinese Medicine for its anti-inflammatory activity, but its efficacy in cerebral ischemia/reperfusion (I/R) injury remains unclear. In a middle cerebral artery occlusion (MCAO) rat model, MCAO rats were administered (Sham group and MCAO model group treated with an equal volume of solvent, NOB group treated with 10 or 20 mg/kg NOB) once a day for 7 days before cerebral ischemia and again after reperfusion, 2,3,5-triphenyltetrazolium chloride (TTC) staining was applied to assess the infarct area. Neurological function was evaluated by the modified neurological severity score and Morris water maze. The levels of inflammatory factors, interleukin 6 (IL-6), interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α), were examined by enzyme-linked immunosorbent assay (ELISA). Histopathological staining evaluated neuron apoptosis in brain tissue. In an oxygen-glucose deprivation PC12 cell (OGD PC12) model, the proliferation, migration and apoptosis of OGD PC12 cells were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and cell migration assays and flow cytometry. The gene and protein expression levels of Ras homolog gene family, member A (Rho A), ras-related C3 botulinum toxin substrate 1 (Rac 1), Rho-associated kinase 1 (ROCK 1), ROCK 2 in the Rho/ROCK pathway were measured by Real-time PCR (RT-PCR), immunohistochemistry and western blot. In rats with cerebral I/R injury, NOB significantly decreased the infarcted area, neuron apoptosis in brain tissue and expressions of IL-6, IL-1β, and TNF-α. It also improved neurological deficits in brain tissue and enhanced learning and memory ability. Further, NOB had a protective effect on OGD PC12 cells, increasing proliferation and migration and decreasing apoptosis. The expressions of Rho A, Rac 1, ROCK 1 and ROCK 2 were high in cerebral I/R injury rats, but were downregulated by NOB in I/R injury rats' brain tissue and OGD PC12 cells. Nobiletin had a neuroprotective effect in rats with cerebral I/R injury, and its potential mechanism is decreasing neuron apoptosis by inhibiting the Rho/ROCK signaling pathway. These results suggest NOB is a promising neuroprotective agent for patients with cerebral ischemia.

Gastrodin improves neuroinflammation-induced cognitive dysfunction in rats by regulating NLRP3 inflammasome

Neuroinflammation is the main pathological mechanism of cognitive dysfunction caused by neurodegenerative diseases, and effective preventive and therapeutic measures are not available. We predicted the key targets of gastrodin’s effects upon neuroinflammation through Network Pharmacology and molecular docking. Then the predicted targets were used to study how gastrodin affected cognitive dysfunction triggered by lipopolysaccharide-induced neuroinflammation in rats and its mechanisms. Three-month-old male rats were intraperitoneally injected with lipopolysaccharide for 3 days (d), 7 d and 14 d respectively. Gastrodin improved learning and memory ability of rats with neuroinflammation. Lipopolysaccharide enhanced the levels of pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, in rat hippocampus, which could be reversed by gastrodin. Gastrodin also inhibited the activation of microglia. Our findings suggested that gastrodin exerted neuroprotective effects in rats with neuroinflammation by impacting the TLR4-NF-kB-NLRP3 pathway. Therefore, gastrodin may be a potential therapeutic agent for neuroinflammation-induced cognitive dysfunction.

Insight into the Neuroprotective Effect of Genistein-3′-Sodium Sulfonate Against Neonatal Hypoxic-Ischaemic Brain Injury in Rats by Bioinformatics

Therapeutic hypothermia (TH) is the only intervention approved for the treatment of neonatal hypoxic-ischaemic encephalopathy (HIE), but its treatment window is narrow (within 6 h after birth), and its efficacy is not ideal. Thus, alternative treatments are urgently needed. Our previous studies showed that genistein-3′-sodium sulfonate (GSS), a derivative of genistein (Gen), has a strong neuroprotective effect in rats with ischaemic stroke, but its role in HIE is unclear. A hypoxia–ischaemia (HI) brain injury model was established in neonatal male Sprague‒Dawley (SD) rats. Twenty-four hours after reperfusion, rats treated with GSS were assessed for cerebral infarction, neurological function, and neuronal damage. RNA-Seq and bioinformatics analysis were used to explore differentially expressed genes (DEGs) and regulated signalling pathways, which were subsequently validated by Western blotting and immunofluorescence. In this study, we found that GSS not only significantly reduced the size of brain infarcts and alleviated nerve damage in rats with HIE but also inhibited neuronal loss and degeneration in neonatal rats with HIE. A total of 2170 DEGs, of which 1102 were upregulated and 1068 were downregulated, were identified in the GSS group compared with the HI group. In an analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) categories, the downregulated DEGs were significantly enriched in the pathways “Phagosome”, “NF-κB signalling”, and “Complement and coagulation cascades”, amongst others. Meanwhile, the upregulated DEGs were significantly enriched in the pathways “Neurodegeneration”, “Glutamatergic synapse”, and “Calcium signalling pathway”, amongst others. These results indicate that GSS intervenes in the process of HIE-induced brain injury by participating in multiple pathways, which suggests potential candidate drugs for the treatment of HIE.Graphical

Proteomics reveals that Di Dang decoction can regulate the Jak2/Stat5 signaling pathway and inhibit apoptosis by reducing the oxidative stress response in rats with acute intracerebral hemorrhagic stroke

Ethnopharmacological relevanceDi Dang decoction (DDD) is a prescription used for the treatment of cerebral hemorrhage. Its use is derived from the theory of typhoid fever, it has an obvious clinical effect and it has been used in the clinic for a long time. The results of early quantitative proteomics and targeted proteomics studies showed that the administration of high-dose DDD 7 days may regulate the expression of the proteins S100A8, S100A9, Col1a1 and Col1a2. The first 3 days after bleeding begins is the critical period for intervention, what occurs within approximately 3 days after AICH is unclear. Aim of the studyTo explore the effects of Di Dang decoction (DDD) on the Jak2/Stat5 signaling pathway and apoptosis-related gene expression in rats with acute hemorrhagic stroke via the oxidative stress response by proteomics to reveal its neuroprotective mechanism. Materials and methodsNinety healthy Sprague–Dawley (SD) rats were randomly divided into the control, model, and low-, medium-, and high-dose DDD groups, with 18 rats in each group. An acute intracerebral hemorrhage (AICH) model was established by injecting autologous blood into the caudate nucleus. The low-, medium- and high-dose groups were intragastrically administered 0.15625 g/mL, 0.3125 g/mL and 0.625 g/mL DDD, respectively, for 1 or 3 days. The control and model groups were given the same amount of normal saline. Neurological deficits were evaluated by the modified neurological severity score (mNSS) test, brain water content was measured to assess brain tissue damage, and pathological changes in the lesion site were observed by hematoxylin and eosin (HE) staining. The cerebral cortex was selected for quantitative proteomics, and >1.2/1 and <1/1.2 were used as the thresholds for upregulated and downregulated proteins, respectively. KEGG pathway and Gene Ontology (GO) enrichment analyses of the differentially expressed proteins were conducted. The levels of the oxidative stress markers malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) were measured by enzyme-linked immunosorbent assay (ELISA). Western blotting was used to assess p-Jak2, Jak2, p-Stat5, Stat5, Bax, Bcl-2, and Caspase-3 protein expression. ResultsCompared with the model group, the group treated with high-dose DDD for 3 days exhibited significant improvements in neurological defects, brain histopathology, and brain edema; reduced the level of MDA and significantly increased the levels of CAT and SOD; significantly decreased p-Jak2 and p-Stat5 protein expression and expression of the pro-apoptotic genes Bax and c-Caspase-3; and significantly increased expression of the anti-apoptotic gene Bcl-2 (all p＜0.05). ConclusionsHigh-dose DDD administration for 3 days reduces the oxidative stress response, regulates the Jak2/Stat5 signaling pathway and inhibits apoptosis to exert a neuroprotective effect in rats with acute hemorrhagic stroke.

Peptide OM-LV20 protects astrocytes against oxidative stress via the ‘PAC1R/JNK/TPH1’ axis

Stroke can lead to severe nerve injury and debilitation, resulting in considerable social and economic burdens. Due to the high complexity of post-injury repair mechanisms, drugs approved for use in stroke are extremely scarce, and thus, the discovery of new antistroke drugs and targets is critical. Tryptophan hydroxylase 1 (TPH1) is involved in a variety of mental and neurobehavioral processes, but its effects on stroke have not yet been reported. Here, we used primary astrocyte culture, quantitative real-time PCR, double immunofluorescence assay, lentiviral infection, cell viability analysis, Western blotting, and other biochemical experiments to explore the protective mechanism of peptide OM-LV20, which previously exhibited neuroprotective effects in rats after ischemic stroke via a mechanism that may involve TPH1. First, we showed that TPH1 was expressed in rat astrocytes. Next, we determined that OM-LV20 impacted expression changes of TPH1 in CTX-TNA2 cells and exhibited a protective effect on the decrease in cell viability and catalase (CAT) levels induced by hydrogen peroxide. Importantly, we also found that TPH1 expression induced by OM-LV20 may be related to the level of change in the pituitary adenylate cyclase-activating peptide type 1 receptor (PAC1R) and to the JNK signaling pathways, thereby exerting a protective effect on astrocytes against oxidative stress. The protective effects of OM-LV20 likely occur via the ‘PAC1R/JNK/TPH1’ axis, thus highlighting TPH1 as a novel antistroke drug target.

Neuroprotective Effects of Berberine Hydrochloride on Methamphetamine-induced Cognitive Dysfunction: Immunohistochemical and Behavioral Studies in Rats.

Methamphetamine (MA) as an addictive psychostimulant drug affects the central nervous system. The current research aimed to evaluate the impact of berberine hydrochloride on improving cognitive function and neuroprotective effects in rats addicted to MA. In this study, 27 male Wistar rats were randomly assigned to three groups, including control, MA addiction, and MA addiction with berberine hydrochloride (100 mg/kg/d) orally during the three weeks of withdrawal. Two groups received self-administered inhaled MA for two weeks (up to 10 mg/kg). Following the experimental procedures, a Morris water maze (MWM) and shuttle box were used to assess memory, and hippocampal sections from the animals were examined for caspase-3, Ki-67, and glial fibrillary acidic protein (GFAP) expression. The obtained results from the Morris water maze (MWM) showed that berberine hydrochloride decreases (P<0.01) the distance moved and the time spent to reach the hidden platform in the four-day learning trails phase and significant differences were observed in the distance moved, spent time, and frequency of motion in target quadrant on probe test day between groups. Berberine hydrochloride also reduced the latency of animals entering the dark chamber in the treated group compared to the control group (P<0.05). A significant decrease in activation of caspases-3, higher percentages of Ki-67 expression, and an increase in glial fibrillary acidic protein (GFAP) expression of cells was observed in the addicted group compared to the berberine-treated and control groups (P<0.05). Administration of berberine hydrochloride for 3 weeks improves cognitive function in MA addiction and it has potential neuroprotective efficacy. Methamphetamine (MA) as an addictive psychostimulant drug affects the central nervous system.The berberine hydrochloride effects on improving cognitive function and neuroprotective.No approved pharmacotherapy, as well as confirmed medication, is available to treat MA abuse. Methamphetamine (MA) is known as a strong addictive stimulant with high addiction and no approved pharmaco-therapy, as well as confirmed medication, is available to treat MA abuse. The study on the long-term effect of MA exposure on cognitive function during an object recognition memory test showed cognitive dysfunction after MA exposure. Berberine can reduce induced amnesia, which can be due to the increased peripheral and central cholinergic neuronal system functions, in addition, the most important mechanism in the protective effect of berberine against amnesia is the inhabitation of inflammation; however, the berberine impact on cells should be more investigated.

Neuroprotective Effects of the Pannexin-1 Channel Inhibitor: Probenecid on Spinal Cord Injury in Rats.

Proinflammatory immune cell subsets constitute the majority in the local microenvironment after spinal cord injury (SCI), leading to secondary pathological injury. Previous studies have demonstrated that inflammasomes act as an important part of the inflammatory process after SCI. Probenecid, an inhibitor of the Pannexin-1 channel, can inhibit the activation of inflammasomes. This article focuses on the effects of probenecid on the local immune microenvironment, histopathology, and behavior of SCI. Our data show that probenecid inhibited the expression and activation of nucleotide-binding oligomerization domain receptor pyrindomain-containing 1 (NLRP1), apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1, interleukin-1β (IL-1β), and caspase-3 proteins associated with inflammasomes, thereby suppressing the proportion of M1 cells. And consequently, probenecid reduced the lesion area and demyelination in SCI. Moreover, the drug increased the survival of motor neurons, which resulted in tissue repair and improved locomotor function in the injured SC. Altogether, existing studies indicated that probenecid can alleviate inflammation by blocking Pannexin-1 channels to inhibit the expression of caspase-1 and IL-1β, which in turn restores the balance of immune cell subsets and exerts neuroprotective effects in rats with SCI.

The dual gastro- and neuroprotective effects of curcumin loaded chitosan nanoparticles against cold restraint stress in rats

Stress is a condition affecting different body systems. Curcumin (CUR) is a natural compound that has various pharmacological benefits. However, its poor oral bioavailability limits its therapeutic value. This study aimed to formulating curcumin loaded chitosan nanoparticles (CS.CUR.NPs) and investigate its gastroprotective and neuroprotective effects in rats subjected to cold restraint stress (CRS), in reference to conventional oral CUR preparation, and explore its underlying mechanism. Treated groups received either CUR or CS.CUR.NPs (100 mg∕kg) orally for 14 days before exposure to CRS. CRS elicited marked behavioral changes and gastric ulcer accompanied by histopathological abnormalities of the brain and stomach along with elevation of pain score. CUR and CS.CUR.NPs improved stress-induced gastric ulcer, cognitive performance, and pain sensation. Mechanistically, CRS disrupts oxidative and inflammatory status of the brain as manifested by high malondialdehyde and IL-6 and low total antioxidant capacity and IL-10, along with high C-reactive protein level. CRS decreased nuclear factor erythroid 2-related factor2 (Nrf2) and increased nuclear factor-kappa B (NF-κB) expressions. Furthermore, brain levels of unphosphorylated signal transducer and activator of transcription3 (U-STAT3) and glial fibrillary acidic protein (GFAP) were upregulated with stress. CUR and CS.CUR.NPs provided beneficial effects against harmful consequences resulting from stress with superior beneficial effects reported with CS.CUR.NPs. In conclusion, these findings shed light on the neuroprotective effect of CUR and CS.CUR.NPs against stress-induced neurobehavioral and neurochemical deficits and protection against stress-associated gastric ulcer. Moreover, we explored a potential crosslink between neuroinflammation, U-STAT3, NF-κB, and GFAP in brain dysfunction resulted from CRS.

Dl-3-n-butylphthalide attenuates brain injury caused by cortical infarction accompanied by cranial venous drainage disturbance

BackgroundCerebral venous disorder may have a harmful effect on ischaemic stroke; however, the underlying mechanism remains to be elucidated. Although Dl-3-n-butylphthalide is a multitarget agent for antiischaemic stroke, its neuroprotective...

Bioactivity-guided isolation of the major anthocyanin from Lycium ruthenicum Murr. fruit and its antioxidant activity and neuroprotective effects in vitro and in vivo.

Lycium ruthenicum Murr. fruit (LRF) is an edible berry known for its rich anthocyanin content. Our previous study has shown that LRF-derived anthocyanins have neuroprotective effects in rats, which may be due to their effective antioxidant activity. Therefore, this study performed online HPLC-DPPH screening as a bioactivity-guided method for the preparative separation of anthocyanins from LRF. Finally, the main fraction was isolated and identified as petunidin-3,5-O-diglucoside (Pn3G5G). Pn3G5G exhibited strong antioxidant capacity during DPPH and ABTS free radical scavenge assays. Furthermore, Pn3G5G exhibited protective effects on Nε-carboxymethyllysine (CML)-treated Neuro-2a cells by enhancing cell viability in a dose-dependent manner. CML-induced apoptosis was also reduced by Pn3G5G potentially by suppressing oxidative stress and inflammation. More importantly, Pn3G5G significantly improved cognitive impairment, neuroinflammation and neuronal apoptosis in D-galactose-induced aging mice. The result suggests the development of Pn3G5G as a healthcare product or a potent dietary supplement with antioxidant and neuroprotective effects.

PH-Responsive Multifunctional Theranostic Rapamycin-Loaded Nanoparticles for Imaging and Treatment of Acute Ischemic Stroke.

Stroke is the second leading cause of death globally and the most common cause of severe disability. Several barriers need to be addressed more effectively to treat stroke, including efficient delivery of therapeutic agents, rapid release at the infarct site, precise imaging of the infarct site, and drug distribution monitoring. The present study aimed to develop a bio-responsive theranostic nanoplatform with signal-amplifying capability to deliver rapamycin (RAPA) to ischemic brain tissues and visually monitor drug distribution. A pH-sensitive theranostic RAPA-loaded nanoparticle system was designed since ischemic tissues have a low-pH microenvironment compared with normal tissues. The nanoparticles demonstrated good stability and biocompatibility and could efficiently load rapamycin, followed by its rapid release in acidic environments, thereby improving therapeutic accuracy. The nano-drug-delivery system also exhibited acid-enhanced magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging signal properties, enabling accurate multimodal imaging with minimal background noise, thus improving drug tracing and diagnostic accuracy. Finally, in vivo experiments confirmed that the nanoparticles preferentially aggregated in the ischemic hemisphere and exerted a neuroprotective effect in rats with transient middle cerebral artery occlusion (tMCAO). These pH-sensitive multifunctional theranostic nanoparticles could serve as a potential nanoplatform for drug tracing as well as the treatment and even diagnosis of acute ischemic stroke. Moreover, they could be a universal solution to achieve accurate in vivo imaging and treatment of other diseases.

Arbutin attenuates monosodium L-glutamate induced neurotoxicity and cognitive dysfunction in rats

Excitotoxicity, oxidative stress, and neuro-inflammation underlie the pathogenesis of neurodegenerative brain disorders. Although L-glutamate is the prime excitatory neurotransmitter involved in diverse brain functions, however, overabundance at synapse can activate cell death mechanisms. Previous studies indicate that arbutin affords relief in metabolic, cardiovascular, and gastrointestinal disorders. Recently, arbutin showed benefits in animal models of epilepsy, Parkinson's disease, and Alzheimer's disease that further expanded its therapeutic potential against brain disorders. In the present study, we aimed to evaluate the potential of arbutin against monosodium L-glutamate (MSG) neurotoxicity in rats. Wistar rats (male, 180–200 g) were administered MSG (4 mg/kg) and arbutin (50 and 100 mg/kg) intraperitoneally for 21 days. Cognitive functions were assessed using elevated plus maze and novel object recognition task. Biochemical parameters of oxidative stress, tumour necrosis factor-α (TNF-α), γ-amino butyric acid (GABA), acetylcholinesterase (AChE) activity, lactate dehydrogenase (LDH), and intracellular cation-levels (Na+, Ca2+, K+) were determined using whole brain. Administration of MSG augmented cation-levels, oxidative stress, inflammation, AChE, and LDH activities, and decreased GABA levels in the brain. Arbutin (50 and 100 mg/kg, i.p.) significantly decreased these biochemical disturbances in the brain of MSG administered rats. Behavioural results showed that MSG triggered cognitive deficits in rats that were significantly attenuated by arbutin. Histopathological findings in hippocampus and cortex revealed neuroprotective outcome of arbutin treatments against MSG. MK-801 and N(G)-nitro-L-arginine methyl ester (L-NAME) enhanced memory and neuroprotective effects in rats treated with arbutin and MSG. Arbutin may afford therapeutic advantages in neurodegenerative brain disorders by suppressing the excitotoxic pathways.

Inhibition of c-JNK/p38MAPK signaling pathway by Apigenin prevents neurobehavioral and neurochemical defects in ethidium bromide-induced experimental model of multiple sclerosis in rats: Evidence from CSF, blood plasma and brain samples

BackgroundMultiple sclerosis (MS) is an idiopathic and autoimmune-mediated neurodegenerative disease that causes demyelination, neuroinflammation, and axonal loss in the central nervous system (CNS). MS is characterized primarily by motor and cognitive impairment. The current study reveals that the overactivation of c-Jun N-terminal kinases (JNKs) and mitogen-activated protein kinases (MAPK) signaling pathways are involved in the pathophysiology of MS. Apigenin (APG) is a naturally active phytoconstituent that shown neuroprotection via downregulating the c-JNK/p38MAPK signaling pathway. PurposeThe current investigation looked at the neuroprotective potential of APG (40–80 mg/kg) on behavioural, molecular, neurochemical, and gross pathological changes in intracerebropeduncle (ICP) ethidium bromide (EB) induced MS-like rats. MethodsIn the present study, 36 rats were used; each group consisted of six Wistar rats (n = 6) treated with 0.1%/10 μl ICP-EB injection for seven days. From the eighth to the 35th day of the experimental protocol schedule, rats were evaluated for neuromuscular abnormalities using an actophotometer, motor deficits using a rotarod test, gait abnormalities using a beam crossing task (BCT), spatial learning, and memory consolidation using a Morris water maze (MWM). In CSF, blood plasma, and brain homogenate samples of EB-induced MS treated rats, neurochemical parameters were also assessed. ResultsAccording to this research's findings, APG modulates the levels of c-JNK/p38MAPK and myelin basic protein in CSF and brain homogenate. Furthermore, APG restored aberrant levels of apoptotic markers (caspase-3, Bax, Bcl-2) in blood plasma and rat brain homogenate and lowered inflammatory cytokines (TNF-α, IL-1β). APG also reduced oxidative stress by increasing antioxidant enzymes and restored neurotransmitter levels. Our finding shows that APG has a neuroprotective effect in rats by improving gross pathological alterations and decreasing demyelination volume. In addition, APG appears to have neuroprotective effects against EB-induced motor dysfunctions in MS rats.

Selective-cerebral-hypothermia-induced neuroprotection against-focal cerebral ischemia/reperfusion injury is associated with an increase in SUMO2/3 conjugation

Selective cerebral hypothermia is considered an effective treatment for neuronal injury after stroke and avoids the complications of general hypothermia. Several recent studies hanve suggested that SUMO2/3 conjugation occurs following cerebral ischemia/reperfusion (I/R) injury. However, the relationship between the cerebral protective effect of selective cerebral hypothermia and SUMO2/3 conjugation remains unclear. In this study, we investigated the effect of selective cerebral hypothermia on SUMO2/3 conjugation during focal cerebral I/R injury. A total of 140 Sprague-Dawley rats were divided into four groups. In the sham group, only the carotid artery was exposed. The endoluminal filament technique was used to induce middle cerebral artery occlusion in the other three groups. After 2 h of occlusion, the filaments were slowly removed to allow blood reperfusion in the I/R group. In the hypothermia (HT) group and normothermia (NT) group, normal saline at 4 °C and 37 °C, respectively , was perfused through the carotid artery, followed by the restoration of blood flow. The results of the modified neurological severity score (mNSS), 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (HE) staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining demonstrated that selective cerebral hypothermia significantly decreased I/R-induced neuronal injury (mNSS, n = 8, 24 h, HT (5.88 ± 2.36) vs. I/R (8.63 ± 3.38), P < 0.05. 48 h, HT (5.75 ± 2.25) vs. I/R (8.5 ± 2.88), P < 0.05. Cerebral infarct volume percentages, n = 5, HT (18.71 ± 2.13) vs. I/R (41.52 ± 2.90), P < 0.01. Cell apoptosis rate, n = 5, 24 h, HT (21.28 ± 2.61) vs. I/R (43.72 ± 4.30), P < 0.05. 48 h, HT (20.50 ± 2.53) vs. I/R (38.94 ± 2.93), P < 0.05). The expression of Ubc9 and conjugated SUMO2/3 proteins was increased at 24 and 48 h after reperfusion in the 3 non-sham groups, and hypothermia further upregulated the expression of Ubc9 and conjugated SUMO2/3 proteins in the HT group. The expression of SENP3 was increased in the NT group and I/R group, while it was decreased in the HT group at 24 and 48 h after reperfusion (Relative quantities, n = 5, Ubc9, 24 h, HT (2.44 ± 0.22) vs. I/R (1.55 ± 0.39), P < 0.05. 48 h, HT (2.69 ± 0.16) vs. I/R (2.25 ± 0.33), P < 0.05. SENP3, 24 h, HT (0.47 ± 0.15) vs. I/R (2.18 ± 0.43), P < 0.05. 48 h, HT (0.72 ± 0.06) vs. I/R (1.51 ± 0.19), P < 0.05. conjugated SUMO2/3 proteins, 24 h, HT (2.84 ± 0.24) vs. I/R (2.51 ± 0.20), P < 0.05. 48 h, HT (2.73 ± 0.13) vs. I/R (2.44 ± 0.13), P < 0.05). Further analysis showed that the variation in SENP3 expression was more obvious than that in Ubc9 under hypothermia intervention in the HT group. These findings suggest that selective cerebral hypothermia could increase SUMO2/3 modification mainly via down-regulating the expression of SENP3, and then exert neuroprotective effects in rats with cerebral I/R injury.