Reproductive status of male rat offspring following exposure to methamphetamine during intrauterine life: An experimental study.

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: 15 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.

Prenatal Methamphetamine Hydrochloride Exposure Leads to Signal Transduction Alteration and Cell Death in the Prefrontal Cortex and Amygdala of Male and Female Rats' Offspring.

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. Herein, we investigated whether prenatal METH exposure with different doses (2 and 5 mg/kg) could influence neuronal cell death and antioxidant level in the different brain regions of adult male and female offspring. Adult male and female Wistar rats prenatally exposed to METH (2 or 5 mg/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) 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). 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 areas of both male and female offspring's brain. Also, we found an elevation in the GSH content of all both mentioned brain areas and catalase activity of PFC in the offspring's brain. These changes were more significant in female offspring. Being prenatally exposed 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.

Geldanamycin Reduces Aß-Associated Anxiety and Depression, Concurrent with Autophagy Provocation.

Neurodegenerative disorders are generally characterized by abnormal aggregation and deposition of specific proteins. Amyloid beta (Aß)-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 Aß injection. In our experiment, 7 days after Aß 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 Aß-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 Aß-injected rats. Thus, we assumed that GA, at least in part, ameliorated Aß-mediated anxiety and depression by inducing autophagy and improving antioxidant defense system.

Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning.

One of the neuropathological hallmarks of Alzheimer's disease (AD) is the accumulation of beta-amyloid peptides (Aß) in senile plaques. Aß-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 Aß (1-42) in CA1 area of hippocampus. The learning and memory of the rats were assessed 7 days after injection of Aß using passive avoidance (PA) task. As potential contributing factors in Aß-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 Aß-injected rats. Our behavioral data suggest that GA pretreatment can significantly suppress memory deficits in Aß-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 TUNEL-positive cells as well. Thus, we conclude that GA exerts its protective effects against Aß (1-42) toxicity and memory deficits, at least in part, by upregulating of Hsp70 and P70S6K.