Aggravation of cognitive impairments in the valproic acid-induced animal model of autism in BALB/c mice infected with Toxoplasma gondii.

PURPOSE: Toxoplasmosis is a disease caused by infection with a type of coccidial protozoan parasite called Toxoplasma gondii. The relationship between toxoplasmosis and cognitive disorders in neurodegenerative diseases has been proven. There is also evidence that children born to Toxoplasma-infected mothers are more likely to develop autism. METHODS: In the present study, Toxoplasma-infected pregnant BALB/c mice were given valproic acid to induce autism in their male offspring, and their social behaviors, learning, and memory were examined. Chronic toxoplasmosis was established in BALB/c mice by intraperitoneal injection of cyst form of T. gondii. To induce autism, 600 mg/kg of valproic acid was injected intraperitoneally into mice on the 12.5th day of pregnancy. The behavioral experiments, such as social interaction, novel object recognition, and passive avoidance tasks, were performed on male offspring at 50 days. RESULTS: Toxoplasma and valproic acid during the embryonic period caused social communication deficits and disrupted recognition memory and avoidance memory in offspring. Our findings showed that administering valproic acid to Toxoplasma-infected mothers exacerbates cognitive disorders in their offspring.

Impact of ketamine administration on chronic unpredictable stress-induced rat model of depression during extremely low-frequency electromagnetic field exposure: Behavioral, histological and molecular study.

OBJECTIVES: In the study, we examined the effects of ketamine and extremely low-frequency electromagnetic fields (ELF-EMF) on depression-like behavior, learning and memory, expression of GFAP, caspase-3, p53, BDNF, and NMDA receptor in animals subjected to chronic unpredictable stress (CUS). METHODS: After applying 21 days of chronic unpredictable stress, male rats received intraperitoneal (IP) of ketamine (5 mg/kg) and then were exposed to ELF-EMF (10-Hz, 10-mT exposure conditions) for 3 days (3 h per day) and behavioral assessments were performed 24 h after the treatments. Instantly after the last behavioral test, the brain was extracted for Nissl staining, immunohistochemistry, and real-time PCR analyses. Immunohistochemistry (IHC) was conducted to assess the effect of ketamine and ELF-EMF on the expression of astrocyte marker (glial fibrillary acidic protein, GFAP) in the CA1 area of the hippocampus and medial prefrontal cortex (mPFC). Also, real-time PCR analyses were used to investigate the impacts of the combination of ketamine and ELF-EMF on the expression of caspase3, p53, BDNF, and NMDA receptors in the hippocampus in rats submitted to the CUS procedure. Results were considered statistically significant when p < .05. RESULTS: Our results revealed that the combination of ketamine and ELF-EMF increased depression-like behavior, increased degenerated neurons and decreased the number of GFAP (+) cells in the CA1 area and mPFC, incremented the expression of caspase-3, and reduced the expression of BDNF in the hippocampus but showed no effect on the expression of p53 and NMDA-R. CONCLUSIONS: These results reveal that combining ketamine and ELF-EMF has adverse effects on animals under chronic unpredictable stress (CUS).

The effects of combined resveratrol and high intensity interval training on the hippocampus in aged male rats: An investigation into some signaling pathways related to mitochondria.

Objectives: High-intensity interval training (HIIT) is a shape of interval training that provides ameliorated athletic capacity and has a good effect on health. Resveratrol is a natural polyphenol abundant in grapes and red wine and has been demonstrated to apply various useful health impacts on the body. This research aimed to evaluate the interactive effects of swimming HIIT and resveratrol consumption on SIRTs 3 & 4, NAD+/NADH, AMPK and SOD2 expression in aged rats. Materials and Methods: In total, forty-five old male albino rats (Wistar) with the age of twenty months were allocated into 5 groups randomly. Control group (Ctrl), Swimming HIIT group (Ex: Exercise), Swimming HIIT with Resveratrol consumption group (R+Ex), Resveratrol consumption group (R) and solvent of resveratrol consumption group (vehicle). R+Ex group accomplished the exercise and consumed resveratrol (10 mg/kg/day, gavage) for 6 weeks. Results: HIIT & resveratrol significantly increased NAD+/NADH, SOD 2 and AMPK in the aged rats. HIIT increased SIRT3, but resveratrol reduced it. As for SIRT4, HIIT decreased it, while resveratrol positively affected it. Conclusion: Resveratrol and HIIT, especially their combination, have anti-oxidant and anti-aging effects on the hippocampus of old rats.

Resveratrol Attenuates Learning, Memory, and Social Interaction Impairments in Rats Exposed to Arsenic.

Arsenic (As) toxicity has deleterious effects on human health causing disorder in the brain. The aim of this study was to investigate the possible neuroprotective effect of resveratrol (RSV) on arsenic-induced neurotoxicity in rats. Neurotoxicity in rats was developed by treating As 10 mg/kg/day for 21 days orally. Animals were put into seven groups: control, vehicle, As, As+RSV10, As+RSV20 mg/kg, RSV10, and RSV20 mg/kg. Behavioral assessments such as the social interaction test, novel object recognition test, elevated plus maze, open field, the Morris water maze, in addition to assessment of biomarkers such as ferric reducing ability of plasma assay, glutathione assay, and malondialdehyde assay, were used to evaluate the effects of RSV on cognitive impairment and molecular changes induced by As. The results showed that cognitive performance impaired in As rats. RSV20 mg/kg significantly could ameliorate behavioral changes like spatial learning in days 3 and 4 (p < 0.05), recognition learning and memory (p < 0.01), disabilities in motor coordination and stress (p < 0.05), increased anxiety (p < 0.05), and social interaction deficit (sociability (p < 0.001) and social memory (p < 0.05)). RSV20 mg/kg also attenuated molecular modifications like decreased antioxidant power (p < 0.001), reduced glutathione content (p < 0.05), and increased malondialdehyde level (p < 0.05) induced by As. In addition to oxidative stress assessments, RSV10 mg/kg could significantly increase FRAP (p < 0.01) and GSH (p < 0.05); however, MDA was not significantly increased. Our current behavioral findings suggest that RSV has neuroprotective effects against AS toxicity.

Ovarian hormones prevent methamphetamine-induced anxiety-related behaviors and neuronal damage in ovariectomized rats.

Methamphetamine (METH) may cause long‒lasting neurotoxic effects and cognitive impairment. On the other hand, the ovarian hormones estrogen and progesterone have neuroprotective effects. In the current study, we aimed to examine the effects of estrogen and progesterone on anxiety‒like behavior and neuronal damage in METH‒exposed ovariectomized (OVX) rats. Three weeks after ovariectomy, the animals received estrogen (1 mg/kg, i.p.), or progesterone (8 mg/kg, i.p.), or estrogen plus progesterone (with the same doses), or vehicle during 7 consecutive days (days 22-28). On day 28, OVX rats were exposed to a single‒day METH regimen (6 mg/kg, four s.c. Injections, with 2 h interval) 30 min after the hormone treatment. The next day (on day 29), the animals were assessed for anxiety‒related behaviors using the open field and elevated plus‒maze tasks. The animals were then sacrificed and brain water content, cell apoptosis and expression of IL-1ß were evaluated. The findings showed that treatment with estrogen or progesterone alone in METH‒exposed rats significantly improved hyperthermia, anxiety‒like behavior, neuronal damage, and inflammation in the CA1 area. Also, treatment with estrogen plus progesterone improved hyperthermia and brain edema. Taken together, the findings suggest that treatment with ovarian hormones can partially prevent hyperthermia and anxiety‒related behaviors induced by METH in OVX rats, which could be accompanied by their neuroprotective effects in the hippocampus.

Chronic Toxoplasma gondii Infection Potentiates Parkinson's Disease Course in Mice Model.

BACKGROUND: Toxoplasma gondii is a neuroinvasive protozoa pathogen that could manipulate its intermediate host's behavior. However, the possible link between T. gondii infection and the development of neurodegenerative disorders such as Parkinson's disease (PD) has been proposed, we tested the hypothesis that in chronic toxoplasmosis neuroinflammation, and molecular mediators potentiate behavioral-cognitive impairments in BALB/c mice with PD. METHODS: To establish chronic toxoplasmosis by Tehran strain, cysts of T. gondii were injected intraperitoneally into BALB/c mice in Kerman, Iran in 2019. To induce the PD model, mice (BALB/c) were treated with Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The behavioral experiments such as anxiety and motor coordination were performed using the Open field and Rotarod tests. Additionally, we investigated the contribution of Toxoplasma-induced neuroinflammation, and behavioral-cognitive impairments in the PD mice model. RESULTS: Chronic toxoplasmosis caused PD-like symptoms and induced various behavioral changes in infected BALB/c mice. In T. gondii infected+MPTP treated group, T. gondii infection could potentiate PD in infected mice receiving MPTP and caused remarkable dysfunction in motor coordination and change in anxiety and depression-like behaviors similar or more severe than PD group. CONCLUSION: Chronic T. gondii infection exacerbates pathological progression of PD in BALB/c mice brain by promoting neuroinflammation, and behavioral changes establishing.

Effect of 4-Fluoro-N-(4-sulfamoylbenzyl) Benzene Sulfonamide on cognitive deficits and hippocampal plasticity during nicotine withdrawal in rats.

Withdrawal from chronic nicotine has damaging effects on a variety of learning and memory tasks. Various Sulfonamides that act as carbonic anhydrase inhibitors have documented role in modulation of various cognitive, learning, and memory processing. We investigated the effects of 4-Fluoro-N-(4-sulfamoylbenzyl) Benzene Sulfonamide (4-FBS) on nicotine withdrawal impairments in rats using Morris water maze (MWM), Novel object recognition, Passive avoidance, and open field tasks. Also, Brain-derived neurotrophic factor (BDNF) profiling and in vivo field potential recording were assessed. Rats were exposed to saline or chronic nicotine 3.8 mg/kg subcutaneously for 14 days in four divided doses, spontaneous nicotine withdrawal was induced by quitting nicotine for 72 h (hrs). Animals received 4-FBS at 20, 40, and 60 mg/kg after 72 h of withdrawal in various behavioral and electrophysiological paradigms. Nicotine withdrawal causes a deficit in learning and long-term memory in the MWM task. No significant difference was found in novel object recognition tasks among all groups while in passive avoidance task nicotine withdrawal resulted in a deficit of hippocampus-dependent fear learning. Anxiety like behavior was observed during nicotine withdrawal. Plasma BDNF level was reduced during nicotine withdrawal as compared to the saline group reflecting mild cognitive impairment, stress, and depression. Withdrawal from chronic nicotine altered hippocampal plasticity, caused suppression of long-term potentiation (LTP) in the CA1 area of the hippocampus. Our results showed that 4-FBS at 40 and 60 mg/kg significantly prevented nicotine withdrawal-induced cognitive deficits in behavioral as well as electrophysiological studies. 4-FBS at 60 mg/kg upsurge nicotine withdrawal-induced decrease in plasma BDNF. We conclude that 4-FBS at 40 and 60 mg /kg effectively prevented chronic nicotine withdrawal-induced impairment in long term potentiation and cognitive performance.

The Combination Effects of Resveratrol and Swimming HIIT Exercise on Novel Object Recognition and Open-field Tasks in Aged Rats.

INTRODUCTION: Resveratrol, a natural polyphenol abundant in grapes and red wine, has been reported to exert numerous beneficial health effects in the body. High-Intensity Interval Exercise (HIIT) is a form of interval training that provides improved athletic capacity and has a protective effect on health. The purpose of this study was to investigate the interactive effects of swimming HIIT and Resveratrol supplementation on behavioral function in Novel object recognition and open-field tests in aged rats. METHODS: A total of 45 aged male Wistar rats with an age of 20 months were randomly assigned into five groups of control (C), swimming HIIT (SW-HIIT), swimming HIIT with Resveratrol supplementation (SW-HIIT-R), Resveratrol supplementation (R), and solvent of Resveratrol supplementation (SR). There was also another group that included young animals (2-month-old) and was used to compare with older animals. Swimming HIIT and Resveratrol supplementation groups performed the exercise and received Resveratrol (10 mg/kg/day, gavage) for six weeks. Novel object recognition and open-field tests were used for evaluating the behavioral functions in animals. RESULTS: The results showed that HIIT and Resveratrol significantly improved recognition memory compared to old animals. Moreover, it seems that HIIT and Resveratrol partly could modulate anxiety-like behaviors compared to old animals in the open-field test.

Cognitive Impairments of Sleep-Deprived Ovariectomized (OVX) Female Rats by Voluntary Exercise.

INTRODUCTION: Previous studies demonstrated that forced and voluntary exercise had ameliorative effects on behavioral tasks followed by Sleep Deprivation (SD) in intact female rats. The main goal of this research was evaluating the impact of voluntary exercise on cognitive functions while SD and ovariectomization is induced in female wistar rats. METHODS: The rats were anesthesized combining dosage of ketamine and xylazine. Then, both ovaries were eliminated and 3 weeks after surgery the animals entered the study. The exercise protocol took 4 weeks of voluntary exercise in a wheel which was connected to home cage. For inducing a 72 hours deprivation the multiple platforms was applied. The cognitive functions were studied by exploiting the Morris Water Maze (MWM) and Novel object recognition tests. Anxiety was evaluated by open field test and corticostrone measurement was carried out by ELISA method. One-way and two-way ANOVA and repeated measures were utilized for data analysis and P<0.05 was considered statistically significant. RESULTS: We observed significant spatial and recognition learning and memory impairments in OVX sleep-deprived rats compared to the control group and voluntary exercise alleviated the SD-induced learning and memory defects. CONCLUSION: We concluded that voluntary exercise can improve cognitive impairments followed by SD in OVX female rats.

Effects of maternal separation on nicotine-induced conditioned place preference and subsequent learning and memory in adolescent female rats.

Adverse early life experiences can potentially increase risk for drug abuse later in life. However, little research has been conducted studying the effects of maternal separation (MS), an experimental model for early life stress, on the rewarding effects of nicotine. Cognitive function may be affected by MS. So, we also investigated whether nicotine administration affect spatial learning and memory in MS adolescent female rats. Rat pups were subjected to daily MS for 15min (MS15) or 180min (MS180) during the first 2 weeks of life or reared under normal animal facility rearing (AFR) conditions. The place preference test was performed with nicotine (0.6mg/kg,s.c.) or vehicle over a period of 6 conditioning trials during adolescence. Spatial learning and memory performance was evaluated by using Morris water maze (MWM). In our study, adolescent female rats exposed to MS180 shown a significantly greater preference for a nicotine-paired compartment during the testing phase than the MS15 group. Nicotine altered the MS-induced spatial learning defects in the MS180 group. These findings suggest that MS may increase sensitivity to the rewarding effects of nicotine and also it is possible to suggest that nicotine administration may influence learning dysfunction induced by MS in adolescent female rats.

Chemical Composition, Anticonvulsant Activity, and Toxicity of Essential Oil and Methanolic Extract of Elettaria cardamomum.

Elettaria cardamomum is an aromatic spice (cardamom) native to the humid Asian areas, which contains some compounds with a potential anticonvulsant activity. Various pharmacological properties such as anti-inflammatory, analgesic, antioxidant, and antimicrobial effects have been related to this plant. This research was conducted to examine the probable protective impact of the essential oil and methanolic extract of E. cardamomum against chemically (pentylentetrazole)- and electrically (maximal electroshock)-induced seizures in mice. In addition, neurotoxicity, acute lethality, and phytochemistry of the essential oil and methanolic extract were estimated. The TLC method showed the presence of kaempferol, rutin, and quercetin in the extract, and the concentration of quercetin in the extract was 0.5 µg/mL. The major compounds in the essential oil were 1,8-cineole (45.6 %), α-terpinyl acetate (33.7 %), sabinene (3.8 %), 4-terpinen-4-ol (2.4 %), and myrcene (2.2 %), respectively. The extract and essential oil showed significant neurotoxicity in the rotarod test at the doses of 1.5 g/kg and 0.75 mL/kg, respectively. No mortalities were observed up to the doses of 2 g/kg and 0.75 mL/kg for the extract and essential oil. The essential oil was effective in both the pentylentetrazole and maximal electroshock models; however, the extract was only effective in the pentylentetrazole model. The study suggested that E. cardamomum methanolic extract had no significant lethality in mice. Both the essential oil and methanolic extract showed movement toxicity. Anticonvulsant effects of E. cardamomum were negligible against the seizures induced by pentylentetrazole and maximal electroshock.

Effects of treatment with estrogen and progesterone on the methamphetamine-induced cognitive impairment in ovariectomized rats.

Methamphetamine (METH) is one of the most powerful psychostimulant that leads to long lasting cognitive impairment. Earlier researches demonstrated that ovarian hormones including estrogen and progesterone ameliorate cognitive function against various central nervous system disorders. Moreover, recent studies demonstrate a neuroprotective role against methamphetamine toxicity. In current study the effects of estrogen and progesterone alone or in combination, on spatial learning and memory in METH-exposed ovariectomized (OVX) rats are investigated. Three weeks after ovariectomy, the animals were treated by estrogen (1mg/kg, i.p.) and progesterone (8mg/kg, i.p.) alone and in combination or vehicle during 14 consecutive days. On the 28th day, rats were exposed to a single-day METH regimens (four injections of 6mg/kg, s.c, at 2h intervals) 30min after the hormones treatment. Finally, spatial learning and memory were examined using the Morris water maze 2days after the last treatment. The findings showed that estrogen and progesterone did not have significant effect on spatial learning and memory in non METH-exposed OVX rats. The treatment with estrogen and progesterone alone in METH-exposed rats, significantly improved spatial learning and memory impairment. On the other hand, the cognitive performance of animals that received combination of estrogen plus progesterone in METH-exposed rats did not significantly differ from that of METH-exposed animals that received vehicle injections. Taken together, the present findings suggest that treatment with ovarian hormones can partially improve spatial learning and memory deficits induced by methamphetamine in OVX rats.

Toxoplasma gondii Infection Promotes Neuroinflammation Through Cytokine Networks and Induced Hyperalgesia in BALB/c Mice.

We hypothesized that in Toxoplasma gondii infection, communication among immune cells promotes neuroinflammation through cytokine networks and induces pain sensitivity under conditions of neuropathic pain. The animal model of Toxoplasma infection was established by the intraperitoneal inoculation of 20-25 tissue cysts from Tehran strain of T. gondii to BALB/c mice. Amitriptyline (20 mg/kg, i.p., 1/day) administrated to animals for 7 days before behavioral tests. Pain behavioral tests including tail flick, hot plate, and formalin test were evaluated in all the groups. The mRNA levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 were examined by real-time PCR. Results revealed that T. gondii induce hyperalgesia in the infected mice, whereas amitriptyline showed a promising effect against the hyperalgesia induced by Toxoplasma infection. The mRNA levels of the aforementioned cytokines significantly (P < 0.05) increased in the infected mice compared to the uninfected ones. Obtained findings suggested that T. gondii infection could promote neuroinflammation through cytokine networks and induced hyperalgesia in BALB/c mice, whereas amitriptyline as an analgesic drug reverses them.