Trial of Lixisenatide in Early Parkinson's Disease.

BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

Mitochondrial protein prohibitin promotes learning memory recovery in mice following intracerebral hemorrhage via CAMKII/CRMP signaling pathway.

Prohibitin (PHB) is a mitochondrial inner membrane protein with neuroprotective, antioxidant, and apoptosis-reducing effects. This study aimed to explore the role of PHB in pathological symptoms, behavioral deficits, and cognitive impairment in a collagenase-IV-induced intracerebral hemorrhage (ICH) murine model. In this study, mice that received collagenase IV injection were pretreated with PHB or saline 21 days prior to modeling. The role of PHB in memory and learning ability was monitored using the Morris water maze, Y-maze, and rotarod, social, startle, and nest-building tests. The effect of PHB on depression-like symptoms was examined using the forced swimming, tail suspension, and sucrose preference tests. Subsequently, mouse samples were analyzed using immunohistochemistry, western blotting, Perls staining, Nissl staining, and gene sequencing. Results showed that collagenase IV significantly induced behavioral deficits, brain edema, cognitive impairment, and depressive symptoms. PHB overexpression effectively alleviated memory, learning, and motor deficits in mice with ICH. PHB markedly inhibited the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive cells and protein levels of ionized calcium-binding adapter molecule 1, glial fibrillary acidic protein, and interleukin-1ß in the perihematomal region of ICH mice. PHB overexpression also remarkably promoted production of neurologin1 (NLGL1), and upregulated levels of Ca2+-calmodulin-dependent kinase II (CaMKII) and collapsin response mediator protein-1 (CRMP1) proteins. In conclusion, PHB overexpression can effectively alleviate the neurological deficits and neurodegeneration around the hematoma region. This may play a protective role by upregulating the expression of NLGL1 and promoting expression of CaMKII and CRMP1.

Why ketamine.

We present the rationale for testing ketamine as an add-on therapy for treating benzodiazepine refractory (established) status epilepticus. In animal studies, ketamine terminates benzodiazepine refractory status epilepticus by interfering with the pathophysiological mechanisms and is a neuroprotectant. Ketamine does not suppress respiration when used for sedation and anesthesia. A Series of reports suggest that ketamine can help terminate refractory and super refractory status epilepticus. We propose to use 1 or 3 mg/Kg ketamine intravenously based on animal-to-human conversion and pharmacokinetic studies. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.

Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

ACEA Attenuates Oxidative Stress by Promoting Mitophagy via CB1R/Nrf1/PINK1 Pathway after Subarachnoid Hemorrhage in Rats.

METHOD: Endovascular perforation was performed to establish a SAH model of rats. ACEA was administered intraperitoneally 1 h after SAH. The CB1R antagonist AM251 was injected intraperitoneally 1 h before SAH induction. Adenoassociated virus- (AAV-) Nrf1 shRNA was infused into the lateral ventricle 3 weeks before SAH induction. Neurological tests, immunofluorescence, DHE, TUNEL, Nissl staining, transmission electron microscopy (TEM), and Western blot were performed. RESULTS: The expression of CB1R, Nrf1, PINK1, Parkin, and LC3II increased and peaked at 24 h after SAH. ACEA treatment exhibited the antioxidative stress and antiapoptosis effects after SAH. In addition, ACEA treatment increased the expression of Nrf1, PINK1, Parkin, LC3II, and Bcl-xl but repressed the expression of Romo-1, Bax, and cleaved caspase-3. Moreover, the TEM results demonstrated that ACEA promoted the formation of mitophagosome and maintained the normal mitochondrial morphology of neurons. The protective effect of ACEA was reversed by AM251 and Nrf1 shRNA, respectively. CONCLUSIONS: This study demonstrated that ACEA alleviated oxidative stress and neurological dysfunction by promoting mitophagy after SAH, at least in part via the CB1R/Nrf1/PINK1 signaling pathway.

Wasp venom from Vespa magnifica acts as a neuroprotective agent to alleviate neuronal damage after stroke in rats.

CONTEXT: Acute ischaemic stroke (AIS) is a major cause of disability and death, which is a serious threat to human health and life. Wasp venom extracted from Vespa magnifica Smith (Vespidae) could treat major neurological disorders. OBJECTIVE: This study investigated the effects of wasp venom on AIS in rats. MATERIAL AND METHODS: We used a transient middle cerebral artery occlusion (MCAO) model in Sprague-Dawley rats (260-280 g, n = 8-15) with a sham operation group being treated as negative control. MCAO rats were treated with wasp venom (0.05, 0.2 and 0.6 mg/kg, i.p.) using intraperitoneal injection. After treatment 48 h, behavioural tests, cortical blood flow (CBF), TTC staining, H&E staining, Nissl staining, TUNEL assay, immunohistochemistry (IHC) and ELISA were employed to investigate neuroprotective effects of wasp venom. RESULTS: Compared with the MCAO group, wasp venom (0.6 mg/kg) improved neurological impairment, accelerated CBF recovery (205.6 ± 52.92 versus 216.7 ± 34.56), reduced infarct volume (337.1 ± 113.2 versus 140.7 ± 98.03) as well as BBB permeability as evidenced by changes in claudin-5 and AQP4. In addition, function recovery of stroke by wasp venom treatment was associated with a decrease in TNF-α, IL-1ß, IL-6 and inhibition activated microglia as well as apoptosis. Simultaneously, the wasp venom regulated the angiogenesis factors VEGF and b-FGF in the brain. CONCLUSIONS: Wasp venom exhibited a potential neuroprotective effect for AIS. In the future, we will focus on determining whether the observed actions were due to a single compound or the interaction of multiple components of the venom.

BMS-470539 Attenuates Oxidative Stress and Neuronal Apoptosis via MC1R/cAMP/PKA/Nurr1 Signaling Pathway in a Neonatal Hypoxic-Ischemic Rat Model.

Neuronal apoptosis induced by oxidative stress plays an important role in the pathogenesis and progression of hypoxic-ischemic encephalopathy (HIE). Previous studies reported that activation of melanocortin-1 receptor (MC1R) exerts antioxidative stress, antiapoptotic, and neuroprotective effects in various neurological diseases. However, whether MC1R activation can attenuate oxidative stress and neuronal apoptosis after hypoxic-ischemic- (HI-) induced brain injury remains unknown. Herein, we have investigated the role of MC1R activation with BMS-470539 in attenuating oxidative stress and neuronal apoptosis induced by HI and the underlying mechanisms. 159 ten-day-old unsexed Sprague-Dawley rat pups were used. HI was induced by right common carotid artery ligation followed by 2.5 h of hypoxia. The novel-selective MC1R agonist BMS-470539 was administered intranasally at 1 h after HI induction. MC1R CRISPR KO plasmid and Nurr1 CRISPR KO plasmid were administered intracerebroventricularly at 48 h before HI induction. Percent brain infarct area, short-term neurobehavioral tests, Western blot, immunofluorescence staining, Fluoro-Jade C staining, and MitoSox Staining were performed. We found that the expression of MC1R and Nurr1 increased, peaking at 48 h post-HI. MC1R and Nurr1 were expressed on neurons at 48 h post-HI. BMS-470539 administration significantly attenuated short-term neurological deficits and infarct area, accompanied by a reduction in cleaved caspase-3-positive neurons at 48 h post-HI. Moreover, BMS-470539 administration significantly upregulated the expression of MC1R, cAMP, p-PKA, Nurr1, HO-1, and Bcl-2. However, it downregulated the expression of 4-HNE and Bax, as well as reduced FJC-positive cells, MitoSox-positive cells, and 8-OHdG-positive cells at 48 h post-HI. MC1R CRISPR and Nurr1 CRISPR abolished the antioxidative stress, antiapoptotic, and neuroprotective effects of BMS-470539. In conclusion, our findings demonstrated that BMS-470539 administration attenuated oxidative stress and neuronal apoptosis and improved neurological deficits in a neonatal HI rat model, partially via the MC1R/cAMP/PKA/Nurr1 signaling pathway. Early administration of BMS-470539 may be a novel therapeutic strategy for infants with HIE.

Combined royal jelly 10-hydroxydecanoic acid and aspirin has a synergistic effect against memory deficit and neuroinflammation.

Alzheimer's disease (AD), the most common form of neurodegenerative dementia among the older population, is associated with acute or chronic inflammation. As a nonsteroidal anti-inflammatory drug, aspirin has recently been widely studied in the prevention and treatment of neurodegenerative diseases. However, there is a controversy about the efficacy as well as the adverse effects of aspirin. 10-Hydroxydecanoic acid (10-HDAA) is a characteristic fatty acid found in the honey bee product royal jelly. In this study, we found that 10-HDAA attenuated the activation of the NF-κB pathway, then targeted Ptgs-1/2, the well-known target of aspirin. Hence, combined therapy of 10-HDAA and aspirin was conducted. In vitro assays suggested that this combinatory group alleviated LPS-induced inflammation in BV-2 cells, as assessed by the downregulation of nitric oxide, COX-2, and IL-6 compared to 10-HDAA or aspirin treatment alone. In vivo assays showed that the combined treatment synergistically inhibited the overactivation of glial cells and decreased the levels of pro-inflammatory mediators. Moreover, 10-HDAA alleviated the adverse effects of aspirin on gastrointestinal injuries and microbiota dysbiosis. The Morris water maze test indicated that neither 10-HDAA nor aspirin effectively improved LPS-induced memory dysfunction, but the combined therapy showed synergistic effects. Altogether, our findings support 10-HDAA and aspirin combinatory therapy as the basis for future therapeutics for AD and other neuroinflammation-related diseases with minimal adverse effects.

The Anxiolytic Drug Buspirone Prevents Rotenone-Induced Toxicity in a Mouse Model of Parkinson's Disease.

A pharmacological and genetic blockade of the dopamine D3 receptor (D3R) has shown to be neuroprotective in models of Parkinson's disease (PD). The anxiolytic drug buspirone, a serotonin receptor 1A agonist, also functions as a potent D3R antagonist. To test if buspirone elicited neuroprotective activities, C57BL/6 mice were subjected to rotenone treatment (10mg/kg i.p for 21 days) to induce PD-like pathology and were co-treated with increasing dosages of buspirone (1, 3, or 10 mg/kg i.p.) to determine if the drug could prevent rotenone-induced damage to the central nervous system (CNS). We found that high dosages of buspirone prevented the behavioural deficits caused by rotenone in the open field test. Molecular and histological analyses confirmed that 10 mg/kg of buspirone prevented the degeneration of TH-positive neurons. Buspirone attenuated the induction of interleukin-1ß and interleukin-6 expression by rotenone, and this was paralleled by the upregulation of arginase-1, brain-derived neurotrophic factor (BDNF), and activity-dependent neuroprotective protein (ADNP) in the midbrain, striatum, prefrontal cortex, amygdala, and hippocampus. Buspirone treatment also improved mitochondrial function and antioxidant activities. Lastly, the drug prevented the disruptions in the expression of two neuroprotective peptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP). These results pinpoint the neuroprotective efficacy of buspirone against rotenone toxicity, suggesting its potential use as a therapeutic agent in neurodegenerative and neuroinflammatory diseases, such as PD.

Comprehensive analysis of lncRNA expression profiles in rats with cerebral ischemia-reperfusion injury after treatment with 20(R)-ginsenoside Rg3.

This study was aimed at investigating the differentially expressions of long noncoding RNAs (lncRNAs) and mRNAs in the brains of a middle cerebral artery occlusion/reperfusion (MCAO/R) group and a MCAO/R + 20(R)-Rg3 group. Biological enrichment analysis was performed, and a lncRNA-mRNA coexpression network was constructed, to reveal the targets and pathways of 20(R)-Rg3 involved in the regulation of cerebral ischemia-reperfusion injury (CIRI). The RNA-seq high-throughput sequencing method was employed to detect differentially-expressed genes between the groups, which were verified by RT-PCR. Functional enrichment analyses of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were performed to explore the biological functions and relevant pathways. The coexpression network of the screened lncRNAs and mRNAs was built by using Cytoscape software. The results identified 77 upregulated lncRNAs, 162 downregulated lncRNAs, 66 upregulated mRNAs and 472 downregulated mRNAs in the MCAO/R + 20(R)-Rg3 group, compared with those in the MCAO/R group. GO enrichment analysis showed that the GO terms were mainly enriched in stimulation response, cellular response, and stress response. KEGG pathways were mainly related to the tumor necrosis factor (TNF), NF-κB, cytokine, and other receptor signaling pathways. In addition, the coexpression analysis between lncRNA and mRNA identified 314 nodes and 515 connections between 6 lncRNAs and 308 mRNAs, of which 511 were positive and 4 were negative. Among them, ENSRNOG-00000059555 was strongly correlated with AABR07001160.1. This study revealed multiple lncRNAs were involved in the neuroprotection of 20(R)-Rg3 against CIRI and thereby provided new insights into the use of 20(R)-Rg3 as a novel neuro protectant in ischemic stroke management.

Preserving Brain LPC-DHA by Plasma Supplementation Attenuates Brain Injury after Cardiac Arrest.

OBJECTIVE: Cardiac arrest (CA) is a major health burden with brain damage being a significant contributor to mortality. We found lysophosphatidylcholine (LPC), including a species containing docosahexaenoic acid (LPC-DHA), was significantly decreased in plasma post-CA, supplementation of which significantly improved neurological outcomes. The aim of this study is to understand the protective role of LPC-DHA supplementation on the brain post-CA. METHODS: We first evaluated associations between the plasma level of LPC-DHA and neurological injury and outcomes of human patients with CA. We then utilized a rat CA model and cell cultures to investigate therapeutic and mechanistic aspects of plasma LPC-DHA supplementation. RESULTS: We found that decreased plasma LPC-DHA was strongly associated with neurological outcomes and disappearance of the difference between gray and white matter in the brain after CA in human patients. In rats, the decreased plasma LPC-DHA was associated with decreased levels of brain LPC-DHA after CA, and supplementing plasma LPC-DHA normalized brain levels of LPC-DHA and alleviated neuronal cell death, activation of astrocytes, and expression of various inflammatory and mitochondrial dynamics genes. We also observed deceased severity of metabolic alterations with LPC-DHA supplementation using untargeted metabolomics analysis. Furthermore, LPC treatment showed a similar protective effect for neurons and astrocytes in mixed primary brain cell cultures. INTERPRETATION: The observed neuroprotection accompanied with normalized brain LPC-DHA level by plasma supplementation implicate the importance of preventing the decrease of brain LPC-DHA post-CA for attenuating brain injury. Furthermore, the data supports the causative role of decreased plasma LPC-DHA for brain damage after CA. ANN NEUROL 2022;91:389-403.

Betaine protects rats against ischemia/reperfusion injury-induced brain damage.

Brain ischemia and reperfusion (I/R) injury may lead to a poor prognosis for ischemic stroke, which could be alleviated by antioxidants with diminished oxidative stress. Betaine is a natural nutrient found in beetroot and seafood to improve cognitive performance in the elderly. The present study investigated whether betaine could protect the brain from I/R injury. Results showed that betaine treatment could reduce H2O2-induced cell death in the PC12 cell line. Pretreatment with betaine reduced the brain infarct volume and neuronal apoptosis in a rat I/R injury model induced by 2-h middle cerebral artery occlusion (MCAO). Biochemical analyses indicated that betaine treatment decreased proinflammatory cytokine production and reduced oxidative stress after I/R injury. Betaine increased the expression of antioxidative enzymes, such as glutathione peroxidase 4 (Gpx4) and superoxide dismutase 1 (Sod1), and antioxidative nonenzymatic genes, such as 3-mercaptopyruvate sulfurtransferase (Mpst), methionine sulfoxide reductases b1 (Msrb1), and Msrb2. These data suggest that betaine exerts a neuroprotective effect in I/R injury through enzymatic and nonenzymatic antioxidative systems and anti-inflammatory mechanisms.NEW & NOTEWORTHY These data suggested that betaine exerted a neuroprotective effect in I/R injury through enzymatic and nonenzymatic antioxidative systems.

Elevated hippocampal mGlut2 receptors in rats with metabolic syndrome-induced-memory impairment, possible protection by vitamin D.

BACKGROUND: Metabolic syndrome patients are commonly prone to major health problems as cardiovascular diseases, diabetes mellitus, chronic kidney disease, cancer and neuropsychological complications including dementia. OBJECTIVES: This research investigates mechanisms linking metabolic syndrome to cognitive impairment and possible impact of vitamin D supplementation. METHODS: Forty male Wistar rats were divided into 4 groups. Control, metabolic syndrome (20% fructose solution in drinking water for 12 weeks, vitamin D supplemented (500 IU/kg/day)) and metabolic syndrome supplemented with vitamin D. Animals were assessed for spatial memory, hippocampal expression of SNAP 25, VAMP and mGlut2 receptor and hippocampus histological examination. Animals with metabolic syndrome showed prolonged acquisition and retention latencies in morris water maze, decreased hippocampal expression of SNAP 25 and VAMP and increased mGlut2 expression. Histologically CA1, CA3 regions and dentate nucleus revealed increase in degenerated neurons and glia cells with decreased pyramidal cell layer thickness. Vitamin D supplementation mitigated alterations induced by metabolic syndrome. CONCLUSIONS: Metabolic syndrome decreased hippocampal synaptic proteins and altered glutamatergic transmission and increased hippocampal neuronal degeneration. Vitamin D supplementation offered neuroprotective effects.

Combination therapy for cerebral ischemia: do progesterone and noscapine provide better neuroprotection than either alone in the treatment?

Ischemic stroke presents multifaceted pathological outcomes with overlapping mechanisms of cerebral injury. High mortality and disability with stroke warrant a novel multi-targeted therapeutic approach. The neuroprotection with progesterone (PG) and noscapine (NOS) on cerebral ischemia-reperfusion (I-R) injury was demonstrated individually, but the outcome of combination treatment to alleviate cerebral damage is still unexplored. Randomly divided groups of rats (n = 6) were Sham-operated, I-R, PG (8 mg/kg), NOS (10 mg/kg), and PG + NOS (8 mg/kg + 10 mg/kg). The rats were exposed to bilateral common carotid artery occlusion, except Sham-operated, to investigate the therapeutic outcome of PG and NOS alone and in combination on I-R injury. Besides the alterations in cognitive and motor abilities, we estimated infarct area, oxidative stress, blood-brain barrier (BBB) permeability, and histology after treatment. Pharmacokinetic parameters like Cmax, Tmax, half-life, and AUC0-t were estimated in biological samples to substantiate the therapeutic outcomes of the combination treatment. We report PG and NOS prevent loss of motor ability and improve spatial memory after cerebral I-R injury. Combination treatment significantly reduced inflammation and restricted infarction; it attenuated oxidative stress and BBB damage and improved grip strength. Histopathological analysis demonstrated a significant reduction in leukocyte infiltration with the most profound effect in the combination group. Simultaneous analysis of PG and NOS in plasma revealed enhanced peak drug concentration, improved AUC, and prolonged half-life; the drug levels in the brain have increased significantly for both. We conclude that PG and NOS have beneficial effects against brain damage and the co-administration further reinforced neuroprotection in the cerebral ischemia-reperfusion injury.

Protective effects of chlorogenic acid on trimethyltin chloride-induced neurobehavioral dysfunctions in mice relying on the gut microbiota.

Trimethyltin chloride (TMT) is acknowledged to have potent neurotoxicity. Chlorogenic acid (CGA), the most abundant polyphenol in the human diet, is well-known for its neuroprotective activity. This investigation was performed to determine the effects and mechanisms of CGA on TMT-induced neurobehavioral dysfunctions. Mice received oral administrations of CGA (30 mg kg-1) for 11 days, in which they were intraperitoneally injected with TMT (2.7 mg kg-1) once on the 8th day. The daily intake of CGA significantly alleviated TMT-induced epilepsy-like seizure and cognition impairment, ameliorating hippocampal neuronal degeneration and neuroinflammation. Oral gavage of CGA potentially exerted neuroprotective effects through JNK/c-Jun and TLR4/NFκB pathways. Microbiome analysis revealed that daily consumption of CGA raised the relative abundance of Lactobacillus in TMT-treated mice. SCFAs, the gut microbial metabolites associated with neuroprotection, were increased in the mouse hippocampus following CGA treatment. TMT-induced neurotransmitter disorders were regulated by oral gavage of CGA, especially DL-kynurenine and acetylcholine chloride. Additionally, neurotransmitters in the mouse hippocampus were found to be highly associated with the gut microbiota. Our findings provided research evidence for the neuroprotective effect of CGA on TMT-induced neurobehavioral dysfunctions.

Neuroprotective effect of exosomes derived from bone marrow mesenchymal stem cells via activating TGR5 and suppressing apoptosis.

Cerebral infarction has become one of the most common neurovascular diseases, and it leads to a high disability and death rate. The exosomes derived from bone marrow mesenchymal stem cells (BM-MSCs-exo) have been viewed as a potential therapeutic method for some diseases. However, the role of BM-MSCs-exo in cerebral infarction remains unclear. Middle cerebral artery occlusion (MCAO) rat and oxygen and glucose deprived cell models were established. Neurological score, animal behaviors, TTC-staining, HE staining, and immunohistochemical staining were performed to evaluate neuro function recovery. Floy cytometry was applied to detect apoptosis and cell cycle. BM-MSCs-exo significantly improved infarction ratio and neurological function after MCAO, and the influence of BM-MSCs-exo on neuro function recovery could be reversed by knocking down TGR5. Meanwhile, BM-MSCs-exo could remarkably activate TGR5 in vivo. The suppression of apoptosis by BM-MSCs-exo in vivo and in vitro was remarkably reversed by siRNA TGR5. BM-MSCs-exo promoted the animal recovery after MCAO. The neuroprotective effect by BM-MSCs-exo might be achieved by activating TGR5 and inhibiting apoptosis. Our findings provide a potential therapeutic thought for the treatment of cerebral infarction through BM-MSCs-exo targeting TGR5 and inhibiting apoptosis.

Pycnogenol ameliorates motor function and gene expressions of NF-ƙB and Nrf2 in a 6-hydroxydopamine-induced experimental model of Parkinson's disease in male NMRI mice.

We investigated the effect of Pycnogenol as an antioxidant on improving motor function, depression, and the expression of NF-ƙB and Nrf2 genes in the experimental model of Parkinson's disease. Forty adult male NMRI mice weighing about 30 g were randomly divided into five groups of eight. Saline group: received 3 µl of saline, as 6-hydroxydopamine (6-OHDA) solvent, unilaterally in the left striatum, treatment groups: first received 3 µl 6-OHDA unilaterally inside the ipsilateral striatum and then divided into subgroup A: received distilled water, Pycnogenol solvent, by gavage for 7 days (lesion group), and subgroup B: received Pycnogenol at doses of 10, 20, and 30 mg/kg by gavage for 7 days. Seven days after Parkinson's model induction, the apomorphine test, the degree of catalepsy by bar test, the duration of immobility (depression) by forced swimming test (FST) were measured. In addition, the expression of NF-ƙB and Nrf2 genes was measured using the real-time PCR technique. The total number of rotations in the apomorphine test decreased significantly in the groups receiving Pycnogenol. Administration of Pycnogenol significantly reduced catalepsy. The study of depression in the group receiving Pycnogenol showed a significant reduction. Also, Pycnogenol increased the expression of the Nrf2 anti-inflammatory gene, but it had no significant difference in the expression of NF-ƙB gene. Pycnogenol, presumably with its antioxidative and genomic effects, improves the expression of the anti-inflammatory gene and found that neuroprotection effect in the brain.