Cell Death In Rat Hippocampus Research Articles

Voluntary alcohol consumption exacerbated high fat diet-induced cognitive deficits by NF-κB-calpain dependent apoptotic cell death in rat hippocampus: Ameliorative effect of melatonin

Modern sedentary lifestyle with altered dietary habits imposes the risk of human health towards several metabolic disorders such as obesity. The metabolic insults negatively affect the mental health status and quality life of affected individuals. Melatonin is a potent antioxidant with anti-inflammatory and neuroprotective properties. The aim of the present study was to investigate the protective effect of melatonin on the cognitive and neurochemical deficits induced by the high-fat diet (HFD) and alcohol (ALC) alone or in combination (HFD + ALC) in rats. Male Wistar rats were given ALC (3-15% i.e. increased gradually) and HFD for 12 weeks in different experimental groups. After 12 weeks, we found that simultaneous consumption of HFD and ALC exacerbates cognitive dysfunction and neurochemical anomalies. However, melatonin (10 mg/kg/day, i.p.) treatment for four weeks significantly prevented memory deficits, oxidative stress and neuroinflammation in HFD, ALC and HFD + ALC groups. RT-PCR analysis showed down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1) in ALC and HFD + ALC groups. Moreover, caspase-3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) mRNA expression level were found up-regulated in hippocampus of HFD, ALC and HFD + ALC groups. However, calpain expression was found up-regulated only in the hippocampus of HFD + ALC group. Chronic treatment with melatonin significantly restored the aberrant gene expression level in HFD, ALC and HFD + ALC group. In conclusion, our findings indicated that melatonin can mitigate the HFD and ALC-induced cognitive deficits via attenuation of oxidative stress and calpain-1 dependent as well as independent caspase-3 mediated neuronal cell death.

Neuroprotective effects of silymarin on ischemia-induced delayed neuronal cell death in rat hippocampus

We examined the effects of silymarin, which was extracted from Silybum marianum, on delayed neuronal cell death in the rat hippocampus. Rats were divided into four groups: sham-operated rats (sham group), rats which underwent ischemic surgery (control group), rats which were treated with silymarin before and after ischemic surgery (pre group), and rats which were treated with silymarin after ischemic surgery only (post group). We performed the ischemic surgery by occluding the bilateral carotid arteries for 20min and sacrificed the rats one week after the surgery. Silymarin was administered orally at 200mg/kg body weight. Smaller numbers of delayed cell deaths were noted in the rat CA1 region of the pre- and post-groups, and no significant difference was observed between these groups. There were few apoptotic cell deaths in all groups. Compared to the control group, significantly fewer cell deaths by autophagy were found in the pre- and post-group. We concluded that silymarin exerts a preservation effect on delayed neuronal cell death in the rat hippocampus and this effect has nothing to do with the timing of administering of silymarin.

Bupropion attenuates kainic acid-induced seizures and neuronal cell death in rat hippocampus

Excessive release of glutamate is believed to be a major component of cell damage following excitotoxicity associated with epilepsy. Bupropion, an atypical antidepressant, has been shown to inhibit glutamate release from rat cerebrocortical nerve terminals. The present study was undertaken to investigate whether bupropion has anti-seizure and anti-excitotoxic effects by using a kainic acid (KA) rat seizure model, an animal model for temporal lobe epilepsy and excitotoxic neurodegeneration. Our results show that bupropion (10 or 50mg/kg), administrated intraperitoneally to the rats 30 min before the KA (15 mg/kg) intraperitoneal injection, increased the seizure latency and decreased the seizure score. Bupropion pretreatment attenuated KA-induced neuronal cell death and microglia activation in the CA3 region of the hippocampus. Furthermore, KA-induced c-Fos expression and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in the hippocampus were also reduced by bupropion pretreatment. These results suggest that bupropion has therapeutic potential in the treatment of seizure and other neurological diseases associated with excitotoxicity.

Radiation-mediated induction of apoptotic cell death in rat hippocampus

Ionizing radiation is commonly used in the treatment of brain tumors but it can impair cognitive functions, such as learning and memory. Since cognitive dysfunctions are predominantly result of cell death by apoptosis in hippocampal cells, in this study we analyzed acute effects of cranial gamma-irradiation (10 Gy) on expression of proapoptotic molecules (p53, Bax) and antiapoptotic molecule Bcl-2, as well as caspase-3 activation and cytochrome c redistribution in the hippocampus of young rats. The selected regimen of irradiation resembles the established animal model for childhood prophylactic cranial radiotherapy. Our results demonstrated that p53 mRNA expression was unchanged after irradiation, while induction of p53 protein was rapid. In parallel, Bax mRNA and protein levels were also increased following irradiation, whereas Bcl-2 expression was not changed during the examined post-irradiation period. These changes were accompanied with early hallmarks of apoptosis, such as increased cytochrome c release and stimulated activation of caspase-3. Overall, this study demonstrates that cranial irradiation is associated with the augmented apoptotic pathway in the rat hippocampus, which could be related to the cognitive decline observed in patients after prophylactic cranial radiotherapy, but also opens perspective in finding radioprotectors that can mitigate radiation injury of normal brain tissue.

Suppression of postsynaptic density protein 95 by antisense oligonucleotides diminishes postischemic pyramidal cell death in rat hippocampal CA1 subfield

Our previous investigation has shown that postsynaptic density protein 95 (PSD-95) is critical for the Src family kinases-mediated tyrosine phosphorylation of N-methyl- d-aspartate receptor subunit 2A (NR2A) in the postischemic hippocampus. To clarify the roles of PSD-95 in the ischemic brain damage, histological method was performed to examine the effects of PSD-95 antisense oligonucleotides (AS) on the postischemic delayed cell death in rat hippocampus. Transient (15 min) brain ischemia was induced by the four-vessel occlusion method in Sprague–Dawley rats. Five days of reperfusion following brain ischemia (I/R5d) led to hippocampal CA1 pyramidal cell death upward of 90%. Intracerebroventricular infusion of AS (every 24 h for 3 days before ischemia) not only decreased the PSD-95 expression but also increased the number of surviving pyramidal neurons, while missense oligonucleotides (MS) had no effects. To further investigate the mechanisms underlying the neuroprotection of PSD-95 deficiency, the interaction of proline-rich tyrosine kinase 2 (Pyk2) with NR2A as well as autophosphorylation (Tyr402) of Pyk2 were detected. Immunoprecipitation and immunoblot analysis showed that preischemic treatment with AS, but not MS or vehicle, attenuated the I/R6h-induced increases in Pyk2–NR2A association and Pyk2 autophosphorylation. The protein levels of NR2A and Pyk2 had no differences under the above conditions. Our data suggest that the recruitments of ion channels and signaling molecules may be involved in the PSD-95 neurotoxicity in the postischemic hippocampus.

A single oral dose of geranylgeranylacetone attenuates kainic acid-induced seizures and neuronal cell death in rat hippocampus

The present study evaluated the potential effect of geranylgeranylacetone (GGA), which is known as an antiulcer agent, against kainic acid (KA)-induced neurotoxicity. Pretreatment with a single oral GGA dose (800 mg/kg, 2 days before KA) significantly attenuated KA-induced seizures and cell death in rat hippocampus. These effects of GGA were prevented by the coinjection of MK801, a noncompetitive N-methyl- d-aspartate glutamate receptor antagonist, which indicates that the protection was indeed mediated by glutamate receptor activation.