One of the neuropathological hallmarks of Alzheimer's disease (AD) is the accumulation of betaamyloid peptides (Aβ) in senile plaques. Aβ-induced oxidative stress is believed to be responsible for degeneration and apoptosis of neurons and consequent cognitive and memory deficits. Here, we investigated the possible neuroprotective effect of the heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA) against amyloid pathogenesis in adult male Wistar rats. GA or vehicle was injected into the lateral cerebral ventricles of rats 24 h before injection of Aβ (1-42) in CA1 area of hippocampus. The learning and memory of the rats were assessed 7 days after injection of Aβ using passive avoidance (PA) task. As potential contributing factors in Aβ-induced memory decline, we evaluated apoptotic markers and also used terminal-transferase UTP nick end labeling (TUNEL) technique to detect apoptosis in the hippocampus of Aβ-injected rats. Our behavioral data suggest that GA pretreatment can significantly suppress memory deficits in Aβ-injected rats. There was also not only a marked increase in Hsp70 level but also upregulated 70 kDa ribosomal protein S6 kinase (p70S6K) in the hippocampus of GA-treated groups with a reduction in apoptotic factors including caspase-3, poly (ADP-ribose) polymerase, Bax/Bcl-2 ratio, and TUNELpositive cells as well. Thus, we conclude that GA exerts its protective effects against Aβ (1-42) toxicity and memory deficits, at least in part, by upregulating of Hsp70 and P70S6K.

Neurodegenerative disorders are generally characterized by abnormal aggregation and deposition of specific proteins. Amyloid beta (Aβ)-associated neurodegenerative disorder is characterized by an oxidative damage that, in turn, leads to some behavioral changes before the establishment of dementia such as depression and anxiety. In the current study, we investigated the effect of heat shock protein 90 inhibitor geldanamycin (GA) administration 24 h before Aβ injection. In our experiment, 7 days after Aβ injection, elevated plus maze and forced swimming test were conducted to assess anxiety and depression-like behaviors. Levels of autophagy markers and malondialdehyde (MDA) and also activity of catalase in the hippocampus of rats were evaluated. Our behavioral analyses demonstrated that GA pretreatment can significantly decrease anxiety- and depression-like behaviors in Aβ-injected rats. Also, levels of autophagy markers including Atg12, Atg7, and LC3-II increased, while MDA level decreased and the activity of catalase increased in rats pretreated with GA compared to Aβ-injected rats. Thus, we assumed that GA, at least in part, ameliorated Aβ-mediated anxiety and depression by inducing autophagy and improving antioxidant defense system.

BackgroundIn the last decade, there has been a great increase in methamphetamine hydrochloride (METH) abuse by pregnant women that exposes fetus and human offspring to a wide variety of developmental impairments that may be the underlying causes of future psychosocial issues. ObjectiveHerein we investigated whether prenatal METH exposure with different doses (2 and 5mg/kg) could in uence neuronal cell death and antioxidant level in the different brain regions of adult male and female offspring. MethodsAdult male and female Sprague-Dawley rats prenatally exposed to METH (2 or 5mg/kg) and/or saline was used in this study. At week 12 adult rats' offspring were decapitated to collect different brain region tissues including amygdala (AMY), anterior cingulate cortex (ACC), and prefrontal cortices (PFC). Western blot analysis was performed to evaluate the apoptosis and autophagy related markers, and enzymatic assay was used to measure the level of catalase and also reduced glutathione (GSH). ResultsOur results showed that METH exposure during pregnancy increased the level of apoptosis (BAX/Bcl-2 and Caspase-3) and autophagy(Beclin-1 and LC3II/LC3I) in the PFC and AMY area of both male and female offspring's brain. Also, we found an elevation in the GSH content of all three mentioned brain areas and catalase activity of PFC in the offspring's brain. ConclusionPrenatally exposure to METH increased cell death at least partly via apoptosis and autophagy in AMY and PFC of male and female offspring's brain, while the antioxidant system tried to protect cells in these regions.

Background: Methamphetamine abuse during pregnancy is associated with maternal and fetal adverse outcomes. Methamphetamine induces reproductive damage in adults; however, its effect has not been studied during pregnancy. Objective: To investigate the effects of methamphetamine exposure during pregnancy on the reproductive system. Materials and Methods: Fifteen pregnant Wistar rats were divided into 3 groups (n = 5/group), they received daily intraperitoneal injections of saline or methamphetamine (5, and 10 mg/kg) from day 10 until the end of pregnancy. One adult male offspring was selected from each dam. Subjects were euthanized, and their testis was removed. Sperm samples from cauda epididymis were analyzed for sperm concentration, morphology, and motility. Terminal deoxynucleotidyl transferase dUTP nick-end labeling assay was used to detect apoptotic cells. Levels of B-cell lymphoma 2 protein (Bcl-2) and Bcl-2 associated X-protein were measured using Western blot. Results: Methamphetamine significantly decreased sperm concentration (5 mg vs. saline: p = 0.001, 10 mg vs. saline: p < 0.001), normal sperm morphology (saline vs. 10 mg: p = 0.001), and motility (p: saline vs. 5 mg = 0.004, 5 mg vs. 10 mg = 0.011, saline vs. 10 mg < 0.001) in a dose-dependent manner. There was a significantly higher number of terminal deoxynucleotidyl transferase dUTP nick-end labeling -positive cells and higher exposure. Moreover, Bcl-2 associated X-protein was increased, and Bcl-2 was decreased in these rats. Conclusion: The present study shows that chronic methamphetamine exposure during intrauterine period can induce apoptosis of seminiferous tubules and decrease sperm quality in adult rats. Moreover, we showed that the intrinsic apoptotic pathway is involved in this process. Further studies are required to identify the complete molecular pathway of these results. Key words: Methamphetamine, Testis, Fertility, Reproduction, Apoptosis, Intrauterine exposure.

Background: In the last decade, there has been a great increase in methamphetamine hydrochloride (METH) abuse by pregnant women that exposes fetus and human offspring to a wide variety of developmental impairments that may be the underlying causes of future psychosocial issues. Objective: Herein we investigated whether prenatal METH exposure with different doses (2 and 5mg/kg) could influence neuronal cell death and antioxidant level in the different brain regions of adult male and female offspring.Methods: Adult male and female Sprague–Dawley rats prenatally exposed to METH (2 or 5mg/kg) and/or saline was used in this study. At week 12 adult rats' offspring were decapitated to collect different brain region tissues including amygdala (AMY), anterior cingulate cortex (ACC), and prefrontal cortices (PFC). Western blot analysis was performed to evaluate the apoptosis and autophagy related markers, and enzymatic assay was used to measure the level of catalase and also reduced glutathione (GSH).Results: Our results showed that METH exposure during pregnancy increased the level of apoptosis (BAX/Bcl-2 and Caspase-3) and autophagy(Beclin-1 and LC3II/LC3I) in the PFC and AMY area of both male and female offspring’s brain. Also, we found an elevation in the GSH content of all three mentioned brain areas and catalase activity of PFC in the offspring's brain. Conclusion: Prenatally exposure to METH increased cell death at least partly via apoptosis and autophagy in AMY and PFC of male and female offspring’s brain, while the antioxidant system tried to protect cells in these regions.