Protective effects of rosmarinic acid against autistic-like behaviors in a mouse model of maternal separation stress: behavioral and molecular amendments.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with worldwide increasing incidence. Maternal separation (MS) stress at the beginning of life with its own neuroendocrine changes can provide the basis for development of ASD. Rosmarinic acid (RA) is a phenolic compound with a protective effect in neurodegenerative diseases. The aim of this study was to determine the effect of RA on autistic-like behaviors in maternally separated mice focusing on its possible effects on neuroimmune response and nitrite levels in the hippocampus. In this study, 40 mice were randomly divided into five groups of control (received normal saline (1 ml/kg)) and MS that were treated with normal saline (1 ml/kg) or doses of 1, 2, and 4 mg/kg RA, respectively, for 14 days. Three-chamber sociability, shuttle box, and marble burying tests were used to investigate autistic-like behaviors. Nitrite level and gene expression of inflammatory cytokines including TNF-α, IL-1ß, TLR4, and iNOS were assessed in the hippocampus. The results showed that RA significantly increased the social preference and social novelty indexes, as well as attenuated impaired passive avoidance memory and the occurrence of repetitive and obsessive behaviors in the MS mice. RA reduced the nitrite level and gene expression of inflammatory cytokines in the hippocampus. RA, probably via attenuation of the nitrite level as well as of the neuroimmune response in the hippocampus, mitigated autistic-like behaviors in maternally separated mice.

Neuroprotective properties of Betulin, Betulinic acid, and Ursolic acid as triterpenoids derivatives: a comprehensive review of mechanistic studies.

Cognitive deficits are the main outcome of neurological disorders whose occurrence has risen over the past three decades. Although there are some pharmacologic approaches approved for managing neurological disorders, it remains largely ineffective. Hence, exploring novel nature-based nutraceuticals is a pressing need to alleviate the results of neurodegenerative diseases, such as Alzheimer's disease (AD) and other neurodegenerative disorders. Some triterpenoids and their derivates can be considered potential therapeutics against neurological disorders due to their neuroprotective and cognitive-improving effects. Betulin (B), betulinic acid (BA), and ursolic acid (UA) are pentacyclic triterpenoid compounds with a variety of biological activities, including antioxidative, neuroprotective and anti-inflammatory properties. This review focuses on the therapeutic efficacy and probable molecular mechanisms of triterpenoids in damage prevention to neurons and restoring cognition in neurodegenerative diseases. Considering few studies on this concept, the precise mechanisms that mediate the effect of these compounds in neurodegenerative disorders have remained unknown. The findings can provide sufficient information about the advantages of these compounds against neurodegenerative diseases.

Protective effects of vanillic acid on autistic-like behaviors in a rat model of maternal separation stress: Behavioral, electrophysiological, molecular and histopathological alterations.

Compounds derived from herbs exhibit a range of biological properties, including anti-inflammatory, antioxidant, and neuroprotective properties. However, the exact mechanism of action of these compounds in various neurological disorders is not fully discovered yet. Herein, the present work detected the effect of Vanillic acid (VA), a widely-used flavoring agent derived from vanillin, on autistic-like behaviors to assess the probable underlying mechanisms that mediate behavioral, electrophysiological, molecular, and histopathological alterations in the rat model of maternal separation (MS) stress. Maternal separated rats were treated with VA (25, 50, and 100 mg/kg interperitoneally for 14 days). In addition, anxiety-like, autistic-like behaviors, and learning and memory impairment were evaluated using various behavioral tests. Hippocampus samples were assessed histopathologically by H&E staining. Levels of malondialdehyde (MDA) and antioxidant capacity (by the FRAP method), as well as nitrite levels, were measured in brain tissue. Moreover, gene expression of inflammatory markers (IL-1ß, TLR-4, TNF-α, and NLRP3) was evaluated in the hippocampus. Electrophysiological alterations were also estimated in the hippocampus by long-term potentiation (LTP) assessments. Results showed that VA reversed the negative effects of MS on behavior. VA increased the diameter and decreased the percentage of dark neurons in the CA3 area. Accordingly, VA decreased MDA and nitrite levels and increased the antioxidant capacity in brain samples and decreased the expression of all inflammatory genes. VA treated rats showed significant improvements in all LTP parameters. This study provided evidence suggesting a possible role for VA in preventing autism spectrum disorder (ASD) by regulating immune signaling.

A mechanistic view on the neurotoxic effects of air pollution on central nervous system: risk for autism and neurodegenerative diseases.

Many reports have shown a strong association between exposure to neurotoxic air pollutants like heavy metal and particulate matter (PM) as an active participant and neurological disorders. While the effects of these toxic pollutants on cardiopulmonary morbidity have principally been studied, growing evidence has shown that exposure to polluted air is associated with memory impairment, communication deficits, and anxiety/depression among all ages. So, these toxic pollutants in the environment increase the risk of neurodegenerative disease, ischemia, and autism spectrum disorders (ASD). The precise mechanisms in which air pollutants lead to communicative inability, social inability, and declined cognition have remained unknown. Various animal model studies show that amyloid precursor protein (APP), processing, oxidant/antioxidant balance, and inflammation pathways change following the exposure to constituents of polluted air. In the present review study, we collect the probable molecular mechanisms of deleterious CNS effects in response to various air pollutants.

Diosmin is neuroprotective in a rat model of scopolamine-induced cognitive impairment.

OBJECTIVE: Scopolamine, a muscarinic cholinergic receptor antagonist, is used as a standard pharmaceutical model for inducing cognitive impairment in animals. Several cognitive behaviors, such as motor function, anxiety, short-term memory, attention are affected by injections of scopolamine. In this study, we have assessed the effects of administration of the diosmin (DM, 50 and 100 mg/kg), before injection of 0.4 mg/kg of scopolamine on memory and motor function, the hippocampal dentate gyrus (DG) electrophysiological activity as well as brain inflammation. METHODS: Eighty male rats were randomly divided into five groups (Control, Veh + scopolamine, DM (50) + scopolamine and DM (100) + scopolamine, donepezil (DP) + scopolamine, n = 16). Scopolamine (0.4 mg/kg, i.p.) is used, in order to induce an animal model of cognitive impairment. Rats pretreated with doses of 50 and 100 mg/kg of DM, 3 mg/kg of DP and/or normal saline for 7 days, before injection of scopolamine. Long-term potentiation (LTP) recording was done for electrophysiological activity assessment. Passive avoidance task (PAT), rotarod and spatial memory tests were evaluated, using a shuttle box, rotarod apparatus and Morris water maze (MWM), respectively. RESULTS: Results indicated that DM at doses of 50 and 100 mg/kg, significantly reversed the LTP (amplitude and slope) impairment of the hippocampal DG neurons, induced by scopolamine. Also, DM at doses of 50 and 100 mg/kg increased the percent of the total time that animals spent in goal quarter, the step-through latency (s) and bar latency time in an animal model of cognitive impairment (p < 0.01 and p < 0.001), respectively. The concentrations of TNF-α in hippocampus of the DM and donepezil groups was significantly lower than the Veh + scopolamine group (p < 0.01). CONCLUSION: This study revealed that the DM is effective in preventing the disruption of synaptic plasticity and cognitive impairments, induced by scopolamine. The positive effects of DM may be mediated through a decline in the TNF- α concentrations in hippocampus as a pro-inflammatory cytokine. Thus, the acquired results suggested that the DM can be used, as a useful and suitable agent for memory restoration, in the treatment of dementia, seen in elderlies.

The regulation of pituitary-thyroid abnormalities by peripheral administration of levothyroxine increased brain-derived neurotrophic factor and reelin protein expression in an animal model of Alzheimer's disease.

Alzheimer's disease (AD) is associated with decreased serum levels of thyroid hormones (THs), increased levels of thyroid-stimulating hormone (TSH), and decreased protein expression of brain-derived neurotrophic factor (BDNF) and reelin in the hippocampus. In this study, we have evaluated the effect of subcutaneous administration of levothyroxine (L-T4) on levels of THs and TSH as well as protein expression of BDNF and reelin in AD rats. To make an animal model of AD, amyloid-beta peptide (Aß) plus ibotenic acid were infused intrahippocampally, and rats were treated with L-T4 and (or) saline for 10 days. The levels of THs and TSH were measured by ELISA kits. Protein synthesis was detected by Western blotting method. Results have been shown that serum level of THs, BDNF, and reelin protein expression in the hippocampus were significantly decreased (P < 0.001) in AD animals and elevated significantly in AD rats treated with L-T4 (P < 0.01). Data showed that TSH level significantly decreased in AD rats treated with L-T4 (P < 0.05). These findings indicated that L-T4 increased BDNF and reelin protein expression by regulation of serum THs and TSH level in Aß-induced AD rats.

Peripheral and central administration of T3 improved the histological changes, memory and the dentate gyrus electrophysiological activity in an animal model of Alzheimer's disease.

The amyloid beta (Aß) induced Alzheimer's disease (AD) is associated with formation the amyloid plaques, cognitive impairments and decline in spontaneous discharge of neurons. In the current study, we evaluated the effect of subcutaneous (S. C) and intrahippocampal (I. H) administrations of triiodothyronine (T3) on the histological changes, memory and the dentate gyrus (DG) electrophysiological activity in an animal model of AD. Eighty adult male Wistar rats (250-300 g) were divided randomly into five groups: Sham-Operated (Sh-O), AD + Vehicle (S. C), AD + Vehicle (I. H), AD+ T3 (S. C) and AD + T3 (I. H). In order to induce animal model of AD, Aß (10 ng/µl, bilaterally) were injected intrahippocampally. Rats were treated with T3 and/or normal saline for 10 days. Passive avoidance and spatial memory were evaluated in shuttle box apparatus and Morris water maze, respectively. Neuronal single unit recording was assessed from hippocampal DG. The percent of total time that animals spent in target quarter, the mean latency time (sec), the step through latency and the average number of spikes/bin were decreased significantly in AD rats compared with the Sh-O group (p < 0.001) and were increased significantly in AD groups that have received T3 (S. C and I. H) in compared with AD group (p < 0.01, p < 0.001). Also, formation of amyloid plaques was decreased in AD rats treated with T3.The results showed that T3 injection (S. C and I. H), by reduction of neural damage and increment of neuronal spontaneous activity improved the memory deficits in Aß-induced AD rats.

Central and peripheral administrations of levothyroxine improved memory performance and amplified brain electrical activity in the rat model of Alzheimer's disease.

Alzheimer's disease (AD) is associated with cognitive impairments and a decline in the spontaneous neuronal discharge. In the current study, we evaluated the effect of subcutaneous (S.C.) and intrahippocampal (I.H.) administrations of levothyroxine (LT-4) on the passive avoidance and spatial memory, as well as electrophysiological activity in an animal model of AD. One hundred-sixty male Wistar rats were divided into two main groups. The S.C. group included two Sham and four AD (vehicle or L-T4 25, 50 & 100µg/kg); and the I.H. had consisted of two Sham and two AD (vehicle or L-T4 10µg/kg) subgroups. To make an animal model of AD, amyloid beta (Aß) plus ibotenic acid (Ibo) were injected I.H. Rats were treated with L-T4 and/or normal saline for ten days. Passive avoidance and spatial memory were evaluated in shuttle box and Morris water maze, respectively. Neuronal single unit recording was assessed from hippocampal dentate gyrus (DG). Results showed that the mean latency time (s) increased significantly (p<0.001) in AD animals and decreased significantly in both S.C. and I.H. L-T4 injected AD animals, compared with the AD group (p<0.001). The percentage of total time that animals spent in goal quarter and the step through latency decreased significantly in AD rats (p<0.001) and increased significantly in both S.C. and I.H. L-T4 injected AD animals in comparison with the AD group (p<0.01, p<0.001). Data showed that the average number of spikes/bin significantly decreased in the AD group (p<0.001). The S.C. and I.H. L-T4 injections in AD rats significantly increased the spike rate in comparison to the AD group (p<0.001). In conclusion, both S.C. and I.H. injections of L-T4 alleviated memory deficits and spontaneous neuronal activity in Aß-induced AD rats. Also, I.H. microinjection of L-T4 had more beneficial effects on memory and neuronal electrophysiological activity in comparison to S.C. administration.