Neuroprotective Effects of Crocin Against Ethanol Neurotoxicity in the Animal Model of Fetal Alcohol Spectrum Disorders.

Several experimental and clinical findings suggest that ethanol consumption during pregnancy activates an oxidative-inflammatory cascade followed by wide apoptotic neurodegeneration within several brain areas, including the hippocampus. Crocin can protect neurons because of its antioxidant, anti-inflammatory, and antiapoptotic effects. This study evaluated the crocin protective impact on ethanol-related neuroinflammation and neuronal apoptosis in the hippocampus of rat pups exposed to alcohol over postnatal days. Ethanol (5.25 g/kg) was administrated in milk solution (27.8 ml/kg) by intragastric intubation 2-10 days after birth. The animals received crocin (15, 30, and 45 mg/kg) 2-10 days after birth. The hippocampus-dependent memory and spatial learning were evaluated 36 days after birth using the Morris water maze task. Further, the concentrations of TNF-α and antioxidant enzymes were determined using ELISA assay to examine the antioxidant and anti-inflammatory activities. Also, immunohistochemical staining was performed to evaluate the glial fibrillary acidic protein (GFAP), Ionized calcium binding adaptor molecule 1(Iba-1), and caspase-3 expression. The administration of crocin significantly attenuated spatial memory impairment (P < 0.01) after ethanol neurotoxicity. Also, crocin led to a significant enhancement in SOD (P < 0.05) and GSH-PX (P < 0.01), whereas it caused a reduction in the TNF-α and MDA concentrations compared to the ethanol group (P < 0.01). Moreover, the hippocampal level of caspase-3 (P < 0.01) and the number of GFAP and Iba-1-positive cells decreased in the crocin group (P < 0.001). Crocin suppresses apoptotic signaling mediated by the oxidative-inflammatory cascade in rat pups exposed to ethanol after birth.

Curcumin attenuates spatial memory impairment by anti-oxidative, anti-apoptosis, and anti-inflammatory mechanism against methamphetamine neurotoxicity in male Wistar rats: Histological and biochemical changes.

OBJECTIVE: Methamphetamine is used extensively around the world as a psychostimulant. The complications related to methamphetamine include methamphetamine-induced neurotoxicity, mainly involving intraneuronal processes, such as oxidative stress and excitotoxicity. Curcumin is effective against neuronal injury due to its antioxidant, anti-inflammatory effects. In this study, we examined the protective effects of curcumin against methamphetamine neurotoxicity. METHODS: Sixty male Wistar rats were divided into the following groups: control (n = 12), DMSO (n = 12), methamphetamine (n = 12), and methamphetamine + curcumin (100 and 200 mg/kg, respectively, intraperitoneal [IP]; n = 12). Neurotoxicity was induced by 40 mg/kg of methamphetamine administrated through 4 injections (4 × 10 mg/kg, q2h, IP). Curcumin (100 and 200 mg/kg) was administered at 7 days after the last methamphetamine injection. By using a Morris water maze task, the hippocampus-dependent memory and spatial learning were evaluated 1 day after the last curcumin injection. Then, the animal brains were isolated for biochemical measurements, as well as glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor protein-1(Iba-1) and caspase-3 immunohistochemical staining. RESULTS: The current study demonstrated that administration of curcumin significantly attenuates spatial memory impairment (P < 0.01) following methamphetamine neurotoxicity. Curcumin caused a significant increase in the levels of superoxide dismutase and glutathione peroxidase (P < 0.05). However, it decreased tumor necrosis factor (TNF-α) (P < 0.05) and malondialdehyde (P < 0.01) levels as compared to the methamphetamine group. Also, curcumin significantly reduced Iba-1 (P < 0. 01), GFAP and caspase-3 positive cells in the hippocampus (P < 0.001). CONCLUSION: Curcumin exerted neuroprotective effects on methamphetamine neurotoxicity because of its antioxidant and anti-inflammatory effect.

Simvastatin attenuates spatial memory impairment via inhibiting microgliosis and apoptotic cell death against ethanol induced neurotoxicity in the developing rat hippocampus.

Ethanol is associated with oxidative stress. Exposure to ethanol during childhood may lead to neurological disorders. Congenital disorders induced by alcohol are mainly caused by an oxidative-inflammatory cascade due to extensive apoptotic neurodegeneration in the brain, particularly in the hippocampus. Simvastatin, which acts as an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), is widely used to manage cardiovascular diseases. Recently, the neuroprotective effects of simvastatin against nervous system disorders have been introduced. In this study, we examined the protective effects of simvastatin on ethanol-related neurotoxicity in the hippocampus of rat pups. Ethanol (5.27 g/kg) in a milk solution (27.8 mL/kg) was administered to male rat pups via intragastric intubation at 2-10 days after birth. Also, 10 and 20 mg/kg of simvastatin were injected to the animals. By using Morris water maze task, the hippocampus-dependent memory and spatial learning was evaluated 36 days after birth. An ELISA assay was performed to investigate the antioxidant and anti-inflammatory effects of simvastatin by measuring the levels of tumor necrosis factor-α (TNF-α), and antioxidant enzymes. To assess the expression levels of Iba1 immunohistochemical staining and caspase-3 immunofluorescence staining was performed. The current study demonstrated that administration of simvastatin significantly attenuates spatial memory impairment (P < 0.01) after ethanol neurotoxicity. Also simvastatin could considerably increase the total superoxide dismutaseand glutathione levels (P < 0.01). Moreover, it was associated with a greater reduction in malondialdehyde (P < 0.05) and TNF-α levels, compared to the ethanol group (P < 0.01). Furthermore, in the simvastatin group, the hippocampal level of caspase-3 and the level of Iba1-positive cells, reduced (P < 0.01). This study demonstrated that apoptotic signaling, mediated by the oxidative-inflammatory cascade, could be inhibited by simvastatin in rat pups with ethanol exposure in the postnatal period.

Obestatin inhibits apoptosis and astrogliosis of hippocampal neurons following global cerebral ischemia reperfusion via antioxidant and anti-inflammatory mechanisms.

OBJECTIVES: Obestatin is a newly discovered peptide with antioxidant activities in different animal models. Recent studies have shown that Obestatin inhibits apoptosis following cardiac ischemia/reperfusion injury. Brain ischemia/reperfusion induces irreversible damage especially in the hippocampus area. This study aimed at examining the protective impact of Obestatin on apoptosis, protein expression and reactive astrogliosis level in hippocampal CA1 region of rat following transient global cerebral ischemia. MATERIALS AND METHODS: Forty-eight male Wistar rats were randomly assigned into 4 groups (sham, ischemia/reperfusion, ischemia/reperfusion+ Obestatin 1, and 5 µg/kg, n=12). Ischemia induced occlusion of both common carotid arteries for 20 min. Obestatin 1 and 5 µg/kg were injected intraperitoneally at the beginning of reperfusion period and 24 and 48 hr after reperfusion. Assessment of the antioxidant enzymes and tumor necrosis factor alpha (TNF-α) was performed by ELISA method. Caspase-3 and glial fibrillary acidic protein (GFAP) proteins expression levels were evaluated by immunohistochemical staining 7 days after ischemia. RESULTS: Based on the result of the current study, lower superoxide dismutase (SOD) and glutathione (GSH) (P<0.05) and higher malondialdehyde (MDA) and TNF-α levels were observed in the ischemia group than those of the sham group (P<0.01). Obestatin treatment could increase both SOD and GSH (P<0.05) and reduce MDA and TNF-α (P<0.05) versus the ischemia group. Moreover, obestatin could significantly decrease caspase-3 and GFAP positive cells in the CA1 region of hippocampus (P<0.01). CONCLUSION: Obestatin exerts protective effects against ischemia injury by inhibition of astrocytes activation and decreases neuronal cell apoptosis via its antioxidant properties.

Obestatin improve spatial memory impairment in a rat model of fetal alcohol spectrum disorders via inhibiting apoptosis and neuroinflammation.

Clinical and experimental evidence have demonstrated that, use of alcohol during pregnancy can interrupt brain development. Alcohol-induced neurocognitive deficits in offspring's are involved with activation of oxidative-inflammatory cascade joined with extensive apoptotic neurodegeneration in different brain regions such as hippocampus. Obestatin is a newly discovered peptide with anti-inflammatory, antioxidant, activities in different animal models. In this study, we aimed to evaluate the protective effects of obestatin on alcohol-induced neuronal apoptosis and neuroinflammation in rat pups with postnatal ethanol exposure. Through intragastric intubation, ethanol (5/27 g/kg/day) was administered in male Wistar rat pups on postnatal days 2-10 (third trimester in humans). The animals received Obestatin (1 and 5 µg/kg, S.C.) on postnatal days 2-10. Thirty-six days after birth, the spatial memory test was performed using Morris water maze test, and then, antioxidant enzymes and TNF-α levels were measured by ELISA assay. The expression level of GFAP and caspase-3 proteins was determined via immunohistochemical staining after the behavioral test. Obestatin significantly improved spatial memory deficits (P < .01), and obestatin treatment could significantly increase glutathione and total superoxide dismutase activity (P < .05), reduce level of malondialdehyde (P < .05) and TNF-α in comparison with the ethanol group (P < .01). It's also reduced caspase-3 level, and decreased GFAP-positive cells in the hippocampus of ethanol-exposed rat pups (P < .01). The result of this study shows the potential involvement of oxidative-inflammatory cascade-mediated apoptotic signaling in cognitive deficits due to postnatal ethanol exposure, the results also indicated the neuroprotective effects of Obestatin on alcohol-related behavioral, biochemical and molecular deficits.

Hydrogen Sulfide Protects Hippocampal Neurons Against Methamphetamine Neurotoxicity Via Inhibition of Apoptosis and Neuroinflammation.

Methamphetamine (METH) known as a highly neurotoxic compound associated with irreversible brain cell damage that results in neurological and psychiatric abnormalities. The mechanisms of METH intoxication mainly involve intraneuronal events including oxidative stress, excitotoxicity, and dopamine oxidation. Based on recent studies, H2S can protect neurons through anti-inflammatory, antioxidant, and antiapoptotic mechanisms. Therefore, we aimed to study the effects of protection of H2S against METH neurotoxicity. The 72 male Wistar rats were randomly allocated into six groups: control (n, 12), H2S (n, 12), METH (n, 12), METH + H2S 1 mg/kg (n, 12), METH + H2S 5 mg/kg (n, 12), and METH + H2S 10 mg/kg (n, 12) groups, (NaHS as a H2S donor; 1, 5, 10 mg/kg). METH neurotoxicity was induced by 40 mg/kg of METH in four intraperitoneal (IP) injections (e.g., 4 × 10 mg/kg q. 2 h, IP). NaHS was administered at 30 min, 24 h, and 48 h after the final injection of METH. Seven days after METH injection, the brains were removed for biochemical assessments, glial fibrillary acidic protein (GFAP), and caspase-3 immunohistochemistry staining. H2S treatment could significantly increase both superoxide dismutase and glutathione (P < 0.01), and a reduction was observed in malondialdehyde (P < 0.05) and TNF-α (P < 0.01) versus the METH group. Moreover, H2S could significantly decrease caspase-3 and GFAP-positive cells in the CA1 region of the hippocampus (P < 0.01) compared to the METH group. According to the findings, H2S makes significant neuroprotective impacts on METH neurotoxicity due to its antioxidant and anti-inflammatory activities.

Crocin Inhibits Apoptosis and Astrogliosis of Hippocampus Neurons Against Methamphetamine Neurotoxicity via Antioxidant and Anti-inflammatory Mechanisms.

Methamphetamine (METH) is a stimulant drug, which can cause neurotoxicity and increase the risk of neurodegenerative disorders. The mechanisms of acute METH intoxication comprise intra-neuronal events including oxidative stress, dopamine oxidation, and excitotoxicity. According to recent studies, crocin protects neurons by functioning as an anti-oxidant, anti-inflammatory, and anti-apoptotic compound. Accordingly, this study aimed to determine if crocin can protect against METH-induced neurotoxicity. Seventy-two male Wistar rats that weighed 260-300 g were randomly allocated to six groups of control (n = 12), crocin 90 mg/kg group (n = 12), METH (n = 12), METH + crocin 30 mg/kg (n = 12), METH + crocin 60 mg/kg (n = 12), and METH + crocin 90 mg/kg (n = 12). METH neurotoxicity was induced by 40 mg/kg of METH in four injections (e.g., 4 × 10 mg/kg q. 2 h, IP). Crocin was intraperitoneally (IP) injected at 30 min, 24 h, and 48 h after the final injection of METH. Seven days after METH injection, the rats' brains were removed for biochemical assessment using the ELISA technique, and immunohistochemistry staining was used for caspase-3 and glial fibrillary acidic protein (GFAP) detection. Crocin treatment could significantly increase superoxide dismutase (P < 0.05) and glutathione (P < 0.01) levels and reduce malondialdehyde and TNF-α in comparison with the METH group (P < 0.05). Moreover, crocin could significantly decline the level of caspase-3 and GFAP-positive cells in the CA1 region (P < 0.01). According to the results, crocin exerts neuroprotective effects on METH neurotoxicity via the inhibition of apoptosis and neuroinflammation.