cytochrome-c-t and Cognitive-Dysfunction

Exenatide could reduce blood glucose and alleviate cognitive dysfunction induced by diabetes mellitus (DM). In the present study, a diabetic model was established in Sprague‑Dawley rats to further explore the mechanism of exenatide on diabetes‑induced cognitive impairment. Notably, the model rats performed poorly in the Morris water maze test and had more apoptotic neurons compared with the control rats. By contrast, exenatide attenuated cognitive impairment and inhibited neuronal apoptosis in the DM rat model. To explore the neuroprotective mechanisms of exenatide, western blotting was performed to detect the expression levels of markers of endoplasmic reticulum stress, including cytochrome c (Cyt‑c), Caspase‑3, JNK and c‑JUN, in hippocampal tissue. Reverse transcription‑quantitative PCR was also performed to measure the mRNA expression levels of Cyt‑c and Caspase‑3. After 16 weeks of treatment, exenatide treatment downregulated Cyt‑c, Caspase‑3, phosphorylated (p)‑JNK and p‑c‑JUN expression in the hippocampal tissue of diabetic rats. Moreover, Cyt‑c, Caspase‑3, JNK and JUN expression levels were detected following treatment with a specific inhibitor of JNK (SP600125). The results revealed that SP600125 had similar inhibitory effects on the JNK pathway and ERS‑related protein expression (Cyt‑t, Caspase‑3, p‑JNK and p‑c‑JUN). These results suggested that exenatide improved cognitive dysfunction in DM rats and that the underlying mechanism may be associated with inhibiting apoptosis by suppressing the activation of JNK/c‑JUN.

Topics: Animals; Apoptosis; Blood Glucose; Body Weight; Caspase 3; Cognitive Dysfunction; Cytochromes c; Diabetes Mellitus, Experimental; Exenatide; Genes, jun; Hippocampus; Insulin; Learning; Male; MAP Kinase Signaling System; Memory; Neurons; Neuroprotective Agents; Rats, Sprague-Dawley

It is well recognized that mitochondrial dysfunction contributes to neurodegeneration occurring in Alzheimer's disease (AD). However, evidences of mitochondrial defects in AD peripheral cells are still inconclusive. Here, some mitochondrial-encoded and nuclear-encoded proteins, involved in maintaining the correct mitochondria machine, were investigated in terms of protein expression and enzymatic activity in peripheral blood mononuclear cells (PBMCs) isolated from AD and Mild Cognitive Impairment (MCI) patients and healthy subjects. In addition mitochondrial DNA copy number was measured by real time PCR. We found some differences and some similarities between AD and MCI patients when compared with healthy subjects. For example, cytochrome C and cytochrome B were decreased in AD, while MCI showed only a statistical reduction of cytochrome C. On the other hand, both AD and MCI blood cells exhibited highly nitrated MnSOD, index of a prooxidant environment inside the mitochondria. TFAM, a regulator of mitochondrial genome replication and transcription, was decreased in both AD and MCI patients' blood cells. Moreover also the mitochondrial DNA amount was reduced in PBMCs from both patient groups. In conclusion these data confirmed peripheral mitochondria impairment in AD and demonstrated that TFAM and mtDNA amount reduction could be two features of early events occurring in AD pathogenesis.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Case-Control Studies; Cell Nucleus; Cognitive Dysfunction; Cytochromes b; Cytochromes c; DNA, Mitochondrial; Female; Gene Dosage; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Mitochondria; Oxidants; Oxidation-Reduction; Real-Time Polymerase Chain Reaction; Superoxide Dismutase

Debate continues about the effect of 3, 4-methylenedioxymethamphetamine (MDMA) on cognitive and mitochondrial function through the CNS. It has been shown that physical exercise has an important protective effect on cellular damage and death. Therefore, we investigated the effect of physical exercise on MDMA-induced impairments of spatial learning and memory as well as MDMA effects on brain mitochondrial function in rats. Male wistar rats underwent short-term (2 weeks) or long-term (4 weeks) treadmill exercise. After completion of exercise duration, acquisition and retention of spatial memory were evaluated by Morris water maze (MWM) test. Rats were intraperitoneally (I.P) injected with MDMA (5, 10, and 15mg/kg) 30min before the first training trial in 4 training days of MWM. Different parameters of brain mitochondrial function were measured including the level of ROS production, mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial outermembrane damage, the amount of cytochrome c release from the mitochondria, and ADP/ATP ratio. MDMA damaged the spatial learning and memory in a dose-dependent manner. Brain mitochondria isolated from the rats treated with MDMA showed significant increase in ROS formation, collapse of MMP, mitochondrial swelling, and outer membrane damage, cytochrome c release from the mitochondria, and finally increased ADP/ATP ratio. This study also found that physical exercise significantly decreased the MDMA-induced impairments of spatial learning and memory and also mitochondrial dysfunction. The results indicated that MDMA-induced neurotoxicity leads to brain mitochondrial dysfunction and subsequent oxidative stress is followed by cognitive impairments. However, physical exercise could reduce these deleterious effects of MDMA through protective effects on brain mitochondrial function.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Brain; Cognitive Dysfunction; Cytochromes c; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Male; Maze Learning; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Swelling; N-Methyl-3,4-methylenedioxyamphetamine; Oxidative Stress; Physical Conditioning, Animal; Rats; Rats, Wistar; Reactive Oxygen Species; Spatial Memory