Protective effect of sinomenine against CCl4-induced acute liver injury through regulation of mitochondrial biogenesis.

Carbon tetrachloride (CCl4)-provoked acute liver injury (ALI) is typified by intensified apoptotic, inflammatory, and oxidative changes besides mitochondrial dysfunction. Sinomenine is an active constituent in the medicinal plant Sinomenium acutum. The main objective of this study was to determine sinomenine-induced hepatoprotection following CCl4 challenge with an emphasis on unraveling the contribution of mitochondrial biogenesis-related factors. To induce ALI, CCl4 was injected i.p. and sinomenine was orally administered at 10, 25, and 50 mg/kg. Serum factors in relation to liver dysfunction were measured in addition to hepatic analysis of apoptotic, mitochondrial biogenesis, oxidative, and inflammatory parameters. Sinomenine pretreatment significantly lowered ALT and AST, MDA, IL-6, apoptosis intensity, and TNF-α and restored mitochondrial biogenesis besides enhancement of SOD, sirtuin-1, and AMPK. Sinomenine also conferred hepatoprotective impact, as was apparent by lower pathologic changes. These effects were accompanied by changes in gene expression for AMPK/sirtuin-1/PGC-1α/PPARγ. The current study showed sinomenine hepatoprotective impact in CCl4-induced ALI that is associated with its regulation of mitochondrial biogenesis and parallel enhancement of AMPK/sirtuin-1.

Promising therapeutic effects of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) in addressing autism spectrum disorder induced by valproic acid.

Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects various regions of the brain. Repetitive transcranial magnetic stimulation (rTMS) is a safe and non-invasive method utilized for stimulating different brain areas. Our objective is to alleviate ASD symptoms using high-frequency rTMS (HF-rTMS) in a rat model of ASD induced by valproic acid (VPA). Methods: In this investigation, we applied HF-rTMS for ASD treatment, focusing on the hippocampus. Behavioral assessments encompassed core ASD behaviors, as well as memory and recognition tests, alongside evaluations of anxiety and stress coping strategies. Additionally, we analyzed oxidative stress and a related inflammation marker, as well as other biochemical components. We assessed brain-derived neurotrophic factor (BDNF), Microtubule-associated protein-2 (MAP-2), and synaptophysin (SYN). Finally, we examined dendritic spine density in the CA1 area of the hippocampus. Results: The results demonstrated that HF-rTMS successfully mitigated ASD symptoms, reducing oxidative stress and improving various biochemical factors, along with an increase in dendritic spine density. Discussion: Collectively, our data suggests that HF-rTMS may effectively alleviate ASD symptoms. These findings could be valuable in clinical research and contribute to a better understanding of the mechanisms underlying ASD.

Acetyl-l-carnitine alleviates valproate-induced autism-like behaviors through attenuation of hippocampal mitochondrial dysregulation.

This study aimed to evaluate the potential benefits of acetyl-L-carnitine (ALCAR) in the context of valproate-induced autism. After prenatal exposure to valproate (VPA; 600 mg/kg, i.p.) on embryonic day 12.5, followed by ALCAR treatment (300 mg/kg on postnatal days 21-49, p.o.), assessment of oxidative stress, mitochondrial membrane potential (MMP), mitochondrial biogenesis, parvalbumin interneurons, and hippocampal volume was conducted. These assessments were carried out subsequent to the evaluation of autism-like behaviors. Hippocampal analysis of oxidative factors (reactive oxygen species and malondialdehyde) and antioxidants (superoxide dismutase, catalase, and glutathione) revealed a burden of oxidative stress in VPA rats. Additionally, mitochondrial biogenesis and MMP were elevated, while the number of parvalbumin interneurons decreased. These changes were accompanied by autism-like behaviors observed in the three-chamber maze, marble burring test, and Y-maze, as well as a learning deficit in the Barnes maze. In contrast, administrating ALCAR attenuated behavioral deficits, reduced oxidative stress, improved parvalbumin-positive neuronal population, and properly modified MMP and mitochondrial biogenesis. Collectively, our results indicate that oral administration of ALCAR ameliorates autism-like behaviors, partly through its targeting oxidative stress and mitochondrial biogenesis. This suggests that ALCAR may have potential benefits ASD managing.

Exploring the molecular mechanisms underlying neuroprotective effect of ellagic acid in okadaic acid-induced Alzheimer's phenotype.

Pomegranate polyphenol ellagic acid has medicinal potential in neurodegenerative disorders. The advantageous effect of this polyphenol in improving cognition in okadaic acid (OA)-instigated murine model with unraveling some modes of its action was assessed. Rats received ICV okadaic acid (OA) and post-treated with oral ellagic acid for 3 weeks (25 and 100 mg/kg/day). Cognition was analyzed in behavioral tasks besides assessment of oxidative, apoptotic, and inflammatory factors in addition to hippocampal histochemical analysis. Ellagic acid at a dose of 100 mg/kg properly attenuated cognitive abnormalities in novel object recognition (NOR), Y maze, and Barnes maze tests. Additionally, ellagic acid diminished hippocampal changes of malondialdehyde (MDA), protein carbonyl, reactive oxygen species (ROS), glutathione (GSH), glutathione peroxidase, superoxide dismutase (SOD), apoptotic factors caspases 1 and 3, tumor necrosis factor α (TNFα), and acetylcholinesterase (AChE) and beta secretase 1 (BACE 1) besides reversal of AMP-activated protein kinase (AMPK) and hyperphosphorylated tau (p-tau). Moreover, lower glial fibrillary acidic protein (GFAP) and less injury of hippocampal CA1 pyramidal neurons were observed upon ellagic acid. To conclude, neuroprotective potential of ellagic acid was shown which is somewhat attributable to its reversal of oxidative, apoptotic, and neuroinflammatory events in addition to proper regulation of AMPK and p-tau.

Efficacy and safety of venlafaxine versus nortriptyline for the preventive treatment of migraine: A double-blind randomized clinical trial.

OBJECTIVE: Migraine, as a primary headache disorder, stands as one of the primary causes of disability worldwide. Consequently, prophylactic treatments are highly recommended for individuals experiencing recurrent migraine episodes. Our study aimed to compare the efficacy and safety profiles of venlafaxine and nortriptyline in the prophylactic management of migraine. METHODS: In this single-center, randomized, double-blind clinical trial, 210 migraine patients were allocated into two groups in a 1:1 ratio. One group received venlafaxine (37.5 mg, orally twice daily), while the other group administered nortriptyline (25 mg, orally once daily). A neurologist documented (1) headache intensity using the Visual Analog Scale (VAS) and 6-point Behavioral Rating Scale (BRS-6), (2) headache frequency (per month), and (3) headache duration (in hours) of participants on days 0, 45, and 90 of the intervention. RESULTS: Following the 90-day intervention, a significant decrease was observed in VAS, BRS-6, frequency, and duration of headaches within both groups (all with p-values <0.001). No difference in VAS, BRS-6, or headache durations was observed between the two groups after 45 and 90 days of treatment (all p-values > 0.05). Although the headache frequency exhibited no difference between the groups after 45 days (p-value = 0.097), a significantly lower frequency in the venlafaxine group was observed at day 90 of the intervention (p-value = 0.011). The reductions in attack parameters in the 0-45- and 0-90-day intervals did not meet statistical significance between the two groups (p-values > 0.05). 77.0 % of the participants in the venlafaxine group and 79.2 % in the nortriptyline group experienced a minimum of 50 % improvement in all attack parameters. Venlafaxine demonstrated a statistically significant lower incidence of adverse reactions in comparison to nortriptyline (p-value = 0.005). A total of 33 adverse drug reactions were documented in the venlafaxine group and 53 in the nortriptyline group, with insomnia observed in the former and xerostomia in the latter as the most prevalent side effects. CONCLUSIONS: Venlafaxine and nortriptyline demonstrate clinically significant and comparable therapeutic efficacy for migraine patients in reducing the intensity, frequency, and duration of headache attacks. Venlafaxine may be preferred to nortriptyline in the context of migraine preventive treatment under comparable conditions due to its lower incidence of adverse effects.

Reversing valproic acid-induced autism-like behaviors through a combination of low-frequency repeated transcranial magnetic stimulation and superparamagnetic iron oxide nanoparticles.

Transcranial magnetic stimulation (TMS) is a neurostimulation device used to modulate brain cortex activity. Our objective was to enhance the therapeutic effectiveness of low-frequency repeated TMS (LF-rTMS) in a rat model of autism spectrum disorder (ASD) induced by prenatal valproic acid (VPA) exposure through the injection of superparamagnetic iron oxide nanoparticles (SPIONs). For the induction of ASD, we administered prenatal VPA (600 mg/kg, I.P.) on the 12.5th day of pregnancy. At postnatal day 30, SPIONs were injected directly into the lateral ventricle of the brain. Subsequently, LF-rTMS treatment was applied for 14 consecutive days. Following the treatment period, behavioral analyses were conducted. At postnatal day 60, brain tissue was extracted, and both biochemical and histological analyses were performed. Our data revealed that prenatal VPA exposure led to behavioral alterations, including changes in social interactions, increased anxiety, and repetitive behavior, along with dysfunction in stress coping strategies. Additionally, we observed reduced levels of SYN, MAP2, and BDNF. These changes were accompanied by a decrease in dendritic spine density in the hippocampal CA1 area. However, LF-rTMS treatment combined with SPIONs successfully reversed these dysfunctions at the behavioral, biochemical, and histological levels, introducing a successful approach for the treatment of ASD.

Neuroprotective Therapeutic Potential of microRNA-149-5p against Murine Ischemic Stroke.

Ischemic stroke resulting from blockade of brain vessels lacks effective treatments, prompting exploration for potential therapies. Among promising candidates, microRNA-149 (miR-149) has been investigated for its role in alleviating oxidative stress, inflammation, and neurodegeneration associated with ischemic conditions. To evaluate its therapeutic effect, male Wistar rats were categorized into five groups, each consisting of 27 rats: sham, MCAO, lentiviral control, lentiviral miR-149, and miR149-5p mimic. Treatments were microinjected intracerebroventricularly (ICV) (right side), and ischemia was induced using middle cerebral artery occlusion (MCAO) procedure. Post-MCAO, neurological function, histopathological changes, blood-brain barrier (BBB) permeability, cerebral edema, and mRNA levels of Fas ligand (Faslg) and glutamate ionotropic NMDA receptor 1 (GRIN1) were assessed, alongside biochemical assays. MiR-149 administration improved neurological function, reduced brain damage, preserved BBB integrity, and attenuated cerebral edema. Upregulation of miR149-5p decreased Faslg and GRIN1 expression in ischemic brain regions. MiR-149 also reduced oxidative stress, enhanced antioxidant activity, decreased caspase-1 and - 3 activity, and modulated inflammatory factors in ischemic brain regions. Moreover, DNA fragmentation as an index of cell death decreased following miR-149 treatment. In conclusion, the study underscores miR-149 potential as a neuroprotective agent against ischemic stroke, showcasing its efficacy in modulating various mechanisms and supporting its candidacy as a promising therapeutic target for innovative strategies in stroke treatment.

Therapeutic Potential of Diosgenin in Amelioration of Carbon Tetrachloride-Induced Murine Liver Injury.

Diosgenin is a sapogenin with antidiabetic, antioxidant, and anti-inflammatory properties. The current study investigated whether diosgenin could ameliorate carbon tetrachloride (CCL4)-induced liver injury. To cause liver injury, CCL4 was injected intraperitoneally twice a week for 8 weeks. Daily oral administration of diosgenin at doses of 20, 40, and 80 mg/kg was started one day before CCL4 injection and continued for 8 weeks. Finally, serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and also albumin were assessed. Catalase and superoxide dismutase (SOD) activities in addition to glutathione (GSH) and malondialdehyde (MDA) levels were also quantified in the liver homogenate and routine histological evaluation was also conducted. Elevated serum levels of liver enzymes and decreased serum level of albumin caused by CCL4 were significantly restored following diosgenin administration at doses of 40 and 80 mg/kg. Long-term administration of CCL4 increased inflammatory and apoptotic factors such as IL-1ß, caspase 3, TNF-α, and IL-6 and decreased SOD and catalase activities as well as GSH level in liver homogenates; while MDA level was increased. Treatment with diosgenin increased SOD and catalase activities and GSH levels in the liver of injured animals. In addition, liver MDA, IL-1ß, caspase 3, TNF-α, and IL-6 level or activity decreased by diosgenin treatment. Additionally, diosgenin aptly prevented aberrant liver histological changes. According to obtained results, diosgenin can dose-dependently diminish CCl4-induced liver functional deficits and histological changes in a dose-dependent manner, possibly due to its antioxidant and anti-inflammation properties, and its beneficial effect is comparable to known hepatoprotective agent silymarin.

Protective Effect of Baclofen on Ovarian Cystogenesis and Morphine-Induced Lipid Profile Change in Female Rats.

Introduction: Morphine induces ovarian cysts that cause obesity and disrupt sex hormone secretion. Baclofen, a gamma-aminobutyric acid receptor agonist, can help regulate sex hormones and reduce harmful blood lipids by protecting against morphine-induced gamma-aminobutyric acid inhibition. We investigated the prophylactic effect of baclofen in rats receiving morphine by comparing with the untreated groups. Materials and Methods: Forty eight female Wistar rats were randomly divided into several groups, including control (saline 1 mL/kg, i.p.), morphine (5 mg/kg, i.p.), baclofen (10, 20, and 30 mg/kg, i.p.), and baclofen (10, 20, and 30 mg/kg) before morphine (5 mg/kg). Twenty four hours after the treatment, blood and serum samples were taken to check the levels of gonadotropins (LH & FSH) and lipid profile. The ovaries and uterus were also studied, and a proinflammatory nitric oxide (NO) diagnostic test was completed. The results were analyzed using analysis of variance (α = 0.05). Results: In comparison with the control group, the levels of LH and not FSH decreased in the morphine group and the number of ovarian cysts was more in the morphine group. These problems were not observed in the group of baclofen alone and baclofen + morphine. However, the triglyceride level increased slightly in the baclofen 30 mg/kg + morphine group. But the LDL level somewhat decreased. The proinflammatory NO system did not show significant activation in the ovary and uterus, except for the baclofen 10 mg/kg + baclofen group. Conclusion: Morphine can cause ovarian cysts by lowering LH but baclofen prophylaxis can protect reproductive properties by adapting major metabolic changes.

Kolaviron neuroprotective effect against okadaic acid-provoked cognitive impairment.

Alzheimer's disease (AD) is acknowledged as the main causative factor of dementia that affects millions of people around the world and is increasing at increasing pace. Okadaic acid (OA) is a toxic compound with ability to inhibit protein phosphatases and to induce tau protein hyperphosphorylation and Alzheimer's-like phenotype. Kolaviron (KV) is a bioflavonoid derived from Garcinia kola seeds with anti-antioxidative and anti-inflammation properties. The main goal of this study was to assess whether kolaviron can exert neuroprotective effect against okadaic acid-induced cognitive deficit. Rats had an intracerebroventricular (ICV) injection of OA and pretreated with KV at 50 or 100 mg/kg and examined for cognition besides histological and biochemical factors. OA group treated with KV at 100 mg/kg had less memory deficit in passive avoidance and novel object discrimination (NOD) tasks besides lower hippocampal levels of caspases 1 and 3, tumor necrosis factor α (TNFα) and interleukin 6 (IL-6) as inflammatory factors, reactive oxygen species (ROS), protein carbonyl, malondialdehyde (MDA), and phosphorylated tau (p-tau) and higher level of acetylcholinesterase (AChE) activity, mitochondrial integrity index, superoxide dismutase (SOD), and glutathione (GSH). Moreover, KV pretreatment at 100 mg/kg attenuated hippocampal CA1 neuronal loss and glial fibrillary acidic protein (GFAP) reactivity as a factor of astrogliosis. In summary, KV was able to attenuate cognitive fall subsequent to ICV OA which is partly mediated through its neuroprotective potential linked to mitigation of tau hyperphosphorylation, apoptosis, pyroptosis, neuroinflammation, and oxidative stress and also improvement of mitochondrial health.