Effects of (S)-3,4-DCPG, an mGlu8 receptor agonist, on hippocampal long-term potentiation at perforant pathway-dentate gyrus synapses in prenatal valproic acid-induced rat model of autism.

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental condition characterized by social interaction deficits, communication impairments, repetitive behaviors, and sensory sensitivities. While the etiology of ASD is multifaceted, abnormalities in glutamatergic neurotransmission and synaptic plasticity have been implicated. This study investigated the role of metabotropic glutamate receptor 8 (mGlu8) in modulating long-term potentiation (LTP) in a rat model of ASD induced by prenatal valproic acid (VPA) exposure. To induce an animal model with autism-like characteristics, pregnant rats received an intraperitoneal injection of 500 mg/kg of sodium valproate (NaVPA) on embryonic day 12.5. High-frequency stimulation was applied to the perforant path-dentate gyrus (PP-DG) synapse to induce LTP, while the mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine (DCPG) was administered into the DG. The results revealed that VPA-exposed rats exhibited reduced LTP compared to controls. DCPG had contrasting effects, inhibiting LTP in controls and enhancing it in VPA-exposed rats. Moreover, reduced social novelty preference index (SNPI) in VPA-exposed rats was reversed by intra-DG administration of S-3,4-DCPG. In conclusion, our study advances our understanding of the complex relationship between glutamatergic neurotransmission, synaptic plasticity, and VPA-induced autism model. The findings suggest that mGlu8 receptor dysfunction plays a role in the impaired synaptic plasticity seen in ASD.

Effect of intrahippocampal microinjection of VU0155041, a positive allosteric modulator of mGluR4, on long term potentiation in a valproic acid-induced autistic male rat model.

The precise cause of autism spectrum disorder (ASD) is not fully understood. Despite the involvement of glutamatergic dysregulation in autism, the specific contribution of mGlu4 receptors to synaptic plasticity remains unclear. Using the positive allosteric modulator VU0155041, we aimed to restore long-term potentiation (LTP) in the perforant path-dentate gyrus (PP-DG) pathway in VPA-induced autistic rat model. High-frequency stimulation was applied to the PP-DG synapse to induce LTP, while the VU0155041 was administered into the DG. Unexpectedly, VU0155041 failed to alleviate the observed LTP reduction in VPA-exposed rats, further resulting in a significant decrease in population spike LTP. This unexpected outcome prompts discussion on the complex nature of mGlu4 receptor modulation, highlighting potential interference with physiological processes underlying synaptic plasticity.

Underlying mechanisms behind the neuroprotective effect of vanillic acid against diabetes-associated cognitive decline: An in vivo study in a rat model.

Hippocampal synaptic dysfunction, oxidative stress, neuroinflammation, and neuronal loss play critical roles in the pathophysiology of diabetes-associated cognitive decline (DACD). The study aimed to investigate the effects of vanillic acid (VA), a phenolic compound, against DACD and explore the potential underlying mechanisms. Following confirmation of diabetes, rats were treated with VA (50 mg/kg/day; P.O.) or insulin (6 IU/rat/day; S.C.) for 8 consecutive weeks. The cognitive performance of the rats was evaluated using passive-avoidance and water-maze tasks. Long-term potentiation (LTP) was induced at hippocampal dentate gyrus (DG) synapses in response to high-frequency stimulation (HFS) applied to the perforant pathway (PP) to evaluate synaptic plasticity. Oxidative stress factors, inflammatory markers, and histological changes were evaluated in the rat hippocampus. This study showed that streptozotocin (STZ)-induced diabetes caused cognitive decline that was associated with inhibition of LTP induction, suppression of enzymatic antioxidant activities, enhanced lipid peroxidation, elevated levels of inflammatory proteins, and neuronal loss. Interestingly, chronic treatment with VA alleviated blood glucose levels, improved cognitive decline, ameliorated LTP impairment, modulated oxidative-antioxidative status, inhibited inflammatory response, and prevented neuronal loss in diabetic rats at a level comparable to insulin therapy. The results suggest that the antihyperglycemic, antioxidative, anti-inflammatory, and neuroplastic properties of VA may be the mechanisms behind its neuroprotective effect against DACD.

p-Coumaric acid ameliorates cognitive and non-cognitive disturbances in a rat model of Alzheimer's disease: The role of oxidative stress and inflammation.

BACKGROUND: Alzheimer's disease (AD) is the most progressive form of neurodegenerative disease resulting in cognitive and non-cognitive deficits. Aluminum is recognized as a risk factor for the etiology, pathogenesis, and progression of AD. The present study was designed to determine the effects of p-coumaric acid (p-CA), a phenolic compound, on spatial cognitive ability and non-cognitive functions and to identify the role of oxidative stress and inflammation in an AD rat model induced by aluminum chloride (AlCl3). METHODS: Both AlCl3 (100 mg/kg/day; P.O.) and p-CA (100 mg/kg/day; P.O.) treatments were given for six consecutive weeks. During the fifth and sixth weeks of the treatment period, the cognitive and non-cognitive functions of the rats were assessed using standard behavioral tests. Additionally, oxidative-antioxidative status, inflammatory markers, and histological changes were evaluated in the cerebral cortex and hippocampal regions of the rats. RESULTS: The results of this study showed that AlCl3 exposure enhanced anxiety-/depression-like behaviors, reduced locomotor/exploratory activities, and impaired spatial learning and memory. These cognitive and non-cognitive disturbances were accompanied by increasing oxidative stress, enhancing inflammatory response, and neuronal loss in the studied brain regions. Interestingly, treatment with p-CA alleviated all the above-mentioned neuropathological changes in the AlCl3-induced AD rat model. CONCLUSION: The findings suggest that both anti-oxidative and anti-inflammatory properties of p-CA may be the underlying mechanisms behind its beneficial effect in preventing neuronal loss and improving cognitive and non-cognitive deficits associated with AD.

Therapeutic Effects of High-Intensity Interval Training Exercise Alone and Its Combination with Ecdysterone Against Amyloid Beta-Induced Rat Model of Alzheimer's Disease: A Behavioral, Biochemical, and Histological Study.

Hippocampal oxidative stress has a vital role in the pathophysiology of Alzheimer's disease (AD)-associated behavioral deficits. Ecdysterone (Ecdy), a natural product and primary steroid hormone, exhibits anti-oxidative and neuroprotective effects. High-intensity interval training (HIIT) has emerged as an effective method for improving physiological brain functions. The present study was designed to investigate the comparative effects of separate and combined HIIT and Ecdy treatment on behavioral functions, hippocampal oxidative status, histological changes in an amyloid-beta (Aß)-induced rat model of AD. Adult male rats were treated simultaneously with HIIT exercise and Ecdy (10 mg/kg/day; P.O.), starting ten days after Aß-injection, and they continued for eight consecutive weeks. At the end of the treatment course, the behavioral functions of the rats were assessed by commonly-used behavioral paradigms. Subsequently, brain samples were collected for histological analysis and hippocampus samples were collected for biochemical analysis. Results illustrated that Aß injection impaired learning and memory performances in both novel object recognition and Barnes maze tests, reduced exploratory/locomotor activities in open field test, enhanced anxiety-like behavior in elevated plus-maze (P < 0.05). These behavioral deficits accompanied hippocampal oxidative stress (decreased total antioxidant capacity content and glutathione peroxidase enzyme activity, increased total oxidant status and malondialdehyde level) and neuronal loss in the cerebral cortex and hippocampus in H&E staining (P < 0.05). HIIT and Ecdy improved anxiety-like behavior, attenuated total oxidant status and malondialdehyde, and prevented the neuronal loss (P < 0.05). However, their combination resulted in a more complete and powerful improvement in all the above-mentioned Aß-related deficits (P < 0.05). Overall, these data provide evidence that a combination of HIIT and Ecdy treatment improves Aß-induced behavioral deficits, possibly through ameliorating hippocampal oxidative status and preventing neuronal loss.

Effects of the combination of high-intensity interval training and Ecdysterone on learning and memory abilities, antioxidant enzyme activities, and neuronal population in an Amyloid-beta-induced rat model of Alzheimer's disease.

AIMS: Oxidative stress and neuronal death are the primary reasons for the progression of amyloid-beta (Aß) deposition and cognitive deficits in Alzheimer's disease (AD). Ecdysterone (ecdy), a common derivative of ecdysteroids, possesses free radical scavenging and cognitive-improving effects. High-intensity interval training (HIIT) can be a therapeutic strategy for improving cognitive decline and oxidative stress. The present study was aimed to evaluate the effect of HIIT exercise and ecdy consumption synergistically on the changes in learning and memory functions, activities of hippocampal antioxidant enzymes, and neuronal population after AD induced by Aß in male rats. MATERIALS AND METHODS: Following ten days of Aß injection, HIIT exercise and ecdy treatment (10 mg/kg/day; P.O.) were initiated and continued for eight consecutive weeks in rats. At the end of the treatment period, the rat's learning and memory functions were assessed using Morris water maze and passive avoidance tests. The activity of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GRx), and changes in neuronal population were evaluated in rats' brains. RESULTS: The results indicated that Aß injection disrupted spatial/passive avoidance learning and memory in both tests, accompanied by a decrease in the SOD and CAT (as endogenous antioxidants) in rats' hippocampus. Additionally, Aß injection resulted in neuronal loss in the cerebral cortex and hippocampus. Although the consumption of ecdy separately improved spatial/passive avoidance learning and memory impairments, recovered hippocampal activity of SOD, CAT, GRx, and prevented the hippocampal neuronal loss, its combination along with HIIT resulted in a more powerful and effective amelioration in all the above-mentioned Aß-neuropathological changes. CONCLUSION: Our results confirm that a combination of HIIT and ecdy treatment could be a promising potential therapeutic option against AD-associated cognitive decline, owing to their free radical scavenging and neuroprotective properties.

Synergistic effects of adipose-derived mesenchymal stem cells and selenium nanoparticles on streptozotocin-induced memory impairment in the rat.

AIMS: Memory impairment is determined to be the most well-known symptom of Alzheimer's disease (AD). Although cell therapy seems is an efficient therapeutic strategy to attenuate the AD-related memory impairment, transplanted cells have a short lifespan and do not survive long term in the recipient animals. Herein, we investigated whether the combination therapy of Selenium nanoparticles (SeNPs) and stem cells attenuates the neurotoxicity in an AD animal model. MATERIAL AND METHODS: The adipose-derived mesenchymal stem cells (AMSCs) were transplanted in the AD model. In addition to cell injections, the animals also received oral administration of SeNPs (0.4 mg/kg) for one month. Recognition memory, cell survival, and BDNF concentration were assessed using the novel object recognition task, immunofluorescence, and ELISA methods. KEY FINDINGS: Our results showed that the combined therapy was more effective in increasing the discrimination index than the administering SeNPs or AMSCs alone. Moreover, SeNPs and stem cells together had the greatest effects in reducing the deposition of Aß and increasing the concentration of BDNF. Ultimately, the survival and proliferation of transplanted cells were more in the group that received stem cells besides SeNPs. SIGNIFICANCE: Taken together, it seems that the transplantation of MSCs combined with SeNPs could achieve better results in the neuroprotection in the AD model than a conventional treatment of SeNPs or stem cells alone.