Mechanisms Underlying Cognitive Impairment Induced by Prenatal Alcohol Exposure

Alcohol is one of the most commonly used illicit substances among pregnant women. Clinical and experimental studies have revealed that prenatal alcohol exposure affects fetal brain development and ultimately results in the persistent impairment of the offspring’s cognitive functions. Despite this, the rate of alcohol use among pregnant women has been progressively increasing. Various aspects of human and animal behavior, including learning and memory, are dependent on complex interactions between multiple mechanisms, such as receptor function, mitochondrial function, and protein kinase activation, which are especially vulnerable to alterations during the developmental period. Thus, the exploration of the mechanisms that are altered in response to prenatal alcohol exposure is necessary to develop an understanding of how homeostatic imbalance and various long-term neurobehavioral impairments manifest following alcohol abuse during pregnancy. There is evidence that prenatal alcohol exposure results in vast alterations in mechanisms such as long-term potentiation, mitochondrial function, and protein kinase activation in the brain of offspring. However, to the best of our knowledge, there are very few recent reviews that focus on the cognitive effects of prenatal alcohol exposure and the associated mechanisms. Therefore, in this review, we aim to provide a comprehensive summary of the recently reported alterations to various mechanisms following alcohol exposure during pregnancy, and to draw potential associations with behavioral changes in affected offspring

The Impact of Metformin on the Development of Hypothyroidism and Cardiotoxicity Induced by Cyclophosphamide, Methotrexate, and Fluorouracil in Rats

Cyclophosphamide (CYP), methotrexate (MTX), and 5-fluorouracil (5-FU) are extensively utilized in the therapeutic management of various malignancies. It is noteworthy, however, that potential chemotherapy-related complications include the occurrence of hypothyroidism and cardiotoxicity. Metformin (MET) is a pharmacological agent for managing type 2 diabetes. It has been reported to mitigate certain toxic manifestations associated with chemotherapy. This study’s primary objective is to investigate MET’s protective effects against hypothyroidism and cardiotoxicity induced by CMF treatment. A total of forty male rats were allocated into four distinct groups, each consisting of ten rats per group. These groups were categorized as follows: saline, MET, CMF, and CMF + MET. The experimental group of rats were administered CMF via intraperitoneal injection, receiving two doses of CMF, and fed MET in their daily drinking water, with a 2.5 mg/mL concentration. Blood samples were collected into EDTA tubes for assessment of TSH, free and total (T4 and T3), troponin I, CK, and CK-MB levels utilizing Electrochemiluminescence Immunoassays (ECI). The saline and MET groups did not exhibit significant alterations in thyroid hormones or cardiotoxic biomarkers. In contrast, in the CMF group, there was a notable reduction in T4, FT4, T3, and FT3 levels but no significant changes in TSH levels; however, troponin I, CK, and CK-MB levels were notably elevated. MET co-treatment with CMF did not ameliorate these effects caused by CMF. In conclusion, CMF treatment induced hypothyroidism and cardiotoxicity in rats, but MET co-treatment did not rescue the reduction of thyroid hormones or the elevation of cardiotoxic biomarkers

Peripherally restricted viral challenge elevates extracellular glutamate and enhances synaptic transmission in the hippocampus

Peripheral infections increase the propensity and severity of seizures in susceptible populations. We have previously shown that intraperitoneal (i.p.) injection of a viral mimic, polyinosinic-polycytidylic acid (PIC), elicits hypersusceptibility of mice to kainic acid (KA)-induced seizures. The present study was undertaken to determine whether this seizure hypersusceptibility entails alterations in glutamate signaling. Female C57BL/6 mice were i.p. injected with PIC, and after 24 hours, glutamate homeostasis in the hippocampus was monitored using the enzyme-based microelectrode arrays. PIC challenge robustly increased the level of resting extracellular glutamate. While presynaptic potassium-evoked glutamate release was not affected, glutamate uptake was profoundly impaired and non-vesicular glutamate release was augmented, indicating functional alterations of astrocytes. Electrophysiological examination of hippocampal slices from PIC-challenged mice revealed a several fold increase in the basal synaptic transmission as compared to control slices. PIC challenge also increased the probability of presynaptic glutamate release as seen from a reduction of paired-pulse facilitation (PPF) and synaptic plasticity as seen from an enhancement of long-term potentiation (LTP). Altogether, our results implicate a dysregulation of astrocytic glutamate metabolism and an alteration of excitatory synaptic transmission as the underlying mechanism for the development of hippocampal hyperexcitability, and consequently seizure hypersusceptibility following peripheral PIC challenge

The Ameliorative Effect of Pioglitazone against Neuroinflammation Caused by Doxorubicin in Rats

Doxorubicin (DOX) is a chemotherapeutic agent that is linked with complications such as cardiotoxicity and cognitive dysfunction, known as chemobrain. Chemobrain affects up to 75% of cancer survivors, and there are no known therapeutic options for its treatment. This study aimed to determine the protective effect of pioglitazone (PIO) against DOX-induced cognitive impairment. Forty Wistar female rats were equally divided into four groups: control, DOX-treated, PIO-treated, and DOX + PIO-treated. DOX was administered at a dose of 5 mg/kg, i.p., twice a week for two weeks (cumulative dose, 20 mg/kg). PIO was dissolved in drinking water at a concentration of 2 mg/kg in the PIO and DOX-PIO groups. The survival rates, change in body weight, and behavioral assessment were performed using Y-maze, novel object recognition (NOR), and elevated plus maze (EPM), followed by estimation of neuroinflammatory cytokines IL-6, IL-1β, and TNF-α in brain homogenate and RT-PCR of a brain sample. Our results showed a survival rate of 40% and 65% in the DOX and DOX + PIO groups, respectively, compared with a 100% survival rate in the control and PIO treatment groups at the end of day 14. There was an insignificant increase in body weight in the PIO group and a significant reduction in the DOX and DOX + PIO groups as compared with the control groups. DOX-treated animals exhibited impairment of cognitive function, and the combination PIO showed reversal of DOX-induced cognitive impairment. This was evidenced by changes in IL-1β, TNF-α, and IL-6 levels and also by mRNA expression of TNF- α, and IL-6. In conclusion, PIO treatment produced a reversal of DOX-induced memory impairment by alleviating neuronal inflammation by modulating the expression of inflammatory cytokines

Effect of Various Intermittent Fasting Protocols on Hyperglycemia-Induced Cognitive Dysfunction in Rats

Diabetes mellitus is a highly prevalent metabolic disorder that causes cognitive decline. Here, we investigated the impact of various intermittent fasting protocols on type 2 diabetes mellitus (T2DM)-induced cognitive dysfunction in a rodent model. Male Sprague–Dawley rats (aged 3 months) were randomly assigned to five groups (n = 6 per group) and T2DM was induced by streptozotocin (60 mg/kg, IM). The control group was untreated. Cognitive function was tested (Y-maze, novel object recognition, and elevated plus maze tests) and glucose was assessed. The T2DM rats exhibited significantly higher blood glucose, which is associated with cognitive dysfunction. Compared to the validated animal model of T2DM in rats, various intermittent fasting protocols decreased blood glucose and improved cognitive function. These results indicate that various intermittent fasting protocols may be a potential strategy for managing the hyperglycemia-associated cognitive dysfunction

Vitamin B17 Ameliorates Methotrexate-Induced Reproductive Toxicity, Oxidative Stress, and Testicular Injury in Male Rats

Methotrexate (MTX; 4-amino-10-methylfolic acid) is a folic acid reductase inhibitor used to treat autoimmune diseases and certain types of cancer. Testicular toxicity resulting from MTX is a significant side effect that may cause subsequent infertility. The present study was conducted to examine the ameliorating effects of vitamin B17 (VitB17) against testicular toxicity induced by MTX in male rats. A total of 50 male albino rats were equally divided into five groups [control group; vitamin B17 group (VitB17) administered VitB17 only; methotrexate group administered MTX only; cotreated group, (VitB17+MTX) and posttreated group (MTX+VitB17)]. In methotrexate group (MTX), a significant decrease was observed in body weight and the testicular weight, as well as the levels of plasma testosterone, luteinizing hormone and follicle-stimulating hormone compared with control. The sperm count, viability, morphology index, total motility, and progressive motility also decreased in MTX rats compared with control. Furthermore, the levels of reduced glutathione, catalase, and superoxide dismutase, as well as proliferating cell nuclear antigen protein expression, in the testicular tissue decreased in MTX compared with control. In addition, MTX caused a significant increase in DNA and tissue damage compared with control. However, VitB17 ameliorated these effects, indicating that it has a preventative and curative effect against MTX-induced reproductive toxicity in male rats. The protective effect of VitB17 may be associated to its antioxidant properties as it possibly acts as a free-radical scavenger and lipid peroxidation inhibitor, as well as its protective effect on the levels of GSH, SOD, and CAT

The impact of chicory (Cichoriumintybus L.) on hemodynamic functions and oxidative stress in cardiac toxicity induced by lead oxide nanoparticles in male rats

Background: A common environmental pollutant, lead can induce toxicity in several organ systems. A range of industrial and/or household materials and products contain lead, and food/liquid ingestion and inhalation are the mechanisms through which lead is introduced into the human body. Objective: Since knowledge about the cardiac toxicity of acute lead nanoparticles is limited, this work sought to shed more light on the issue by investigating the therapeutic effects of chicory extract based on rat models to elevate cardiac functions and oxidative stress. Methods: Four research groups were used, each consisting of ten albino rats of male sex and adult age. The groups were: control group, chicory group, lead oxide nanoparticle group, and lead oxide nanoparticle + chicory group. Results: Compared to the control and chicory groups, the lead oxide nanoparticle group displayed a notable increase in heart functions and oxidative stress markers as well as alterations in cardiac histological structure. On the other hand, cardiac function modifications were counteracted through four-week administration of lead oxide nanoparticles alongside chicory. Conclusion: Heart damage caused by lead oxide nanoparticles may be attenuated by chicory through scavenging of free radicals

Neuroprotective Effect of Clobenpropit against Lipopolysaccharide-Induced Cognitive Deficits via Attenuating Neuroinflammation and Enhancing Mitochondrial Functions in Mice

Clobenpropit (CLO), an antagonist on histamine H3 receptors (HH3R), has been shown to protect NMDA-induced neuronal necrosis in cortical neuronal cell culture from rats. In this work, we explored its potential on lipopolysaccharide (LPS)-induced memory deficits, neuroinflammation, and mitochondrial dysfunction in mice. CLO (1 and 3 mg/kg, p.o.) was treated continually for 30 days, and neurotoxicity was induced by four doses of LPS (250 µg/kg, i.p.). The radial arm maze (RAM) was used to access memory behaviors. After the REM test, brain tissue was collected from each mouse to estimate pro-inflammatory cytokines (TNFα and IL6), anti-inflammatory cytokines (TGF-β1 and IL-10), cyclooxygenase-2 (COX 2), and mitochondrial respiratory chain complex (MRCC- I, II and IV) enzymes. CLO treatment reversed the LPS-induced behavioral deficits by a significant reduction in time taken to consume all five bites (TTB), working memory error (WME), and reference memory error (REM) in the REM test. Regarding neuroinflammation, it attenuated the release of COX, TNF-α, and IL-6, and augmented TGF-β1 and IL-10 levels in the brain. Reversal of LPS-induced brain MRCC (I, II, and IV) levels also resulted with CLO treatment. From these findings, CLO promises neuroprotection against LPS-induced cognitive deficits by ameliorating neuroinflammation and restoring the MRCC enzymes in mice

Comparative evaluation of doxorubicin, cyclophosphamide, 5-fluorouracil, and cisplatin on cognitive dysfunction in rats: Delineating the role of inflammation of hippocampal neurons and hypothyroidism

Chemotherapeutic agents such as doxorubicin, cyclophosphamide, fluorouracil, and cisplatin are commonly used to treat a variety of cancers and often result in chemobrain, which manifests as difficulties in learning and memory processes that can persist in the years following treatment. The current study aims to evaluate the cognitive function following treatment with these agents and the underlying mechanisms using a rat model of neuroinflammation and possible implication of thyroid toxicity in chemotherapy induced cognitive dysfunction. Wistar female rats were treated with a single dose of doxorubicin (DOX, 25 mg/kg), 5-fluorouracil (5-FU, 100 mg/kg), cisplatin (8 mg/kg), and cyclophosphamide (CYP, 200 mg/kg) by intraperitoneal injection. The cognitive performance of rats was then evaluated in spatial memory tasks using the Y-maze, novel object recognition (NOR), and elevated plus maze (EPM) tests. Serum levels of thyroid hormones (T3, T4, FT3, and FT4) and thyroid stimulating hormone (TSH) were measured, followed by estimation of TNFα, IL-6, and IL-1β in the hippocampal tissue. Results revealed that all the chemotherapeutic agents produced impairment of cognitive function, and significant increase of pro-inflammatory cytokines such as TNFα, IL-6 and IL-1β in the hippocampal tissues. There was a significant reduction in thyroid hormones (T3, FT3, and T4) and an increase in thyroid stimulating hormone (TSH) in serum, which may also have contributed to the decline in cognitive function. In conclusion, DOX, 5-FU, CYP, and cisplatin produces impairment of spatial memory possibly by inflammation of hippocampal neurons and endocrine disruption (hypothyroidism) in rats