Dose concentration and spatial memory and brain mitochondrial function association after 3,4-methylenedioxymethamphetamine (MDMA) administration in rats.

MDMA-induced impairments of memory performance have been reported in different human and animal studies. However, the correlation between spatial memory impairment, brain mitochondrial function, and concentrations of MDMA and its metabolites has not yet been investigated despite it being needed for comparison with human studies. Therefore, the aim of this study was to investigate the dose concentration and spatial memory as well as brain mitochondrial function association after MDMA administration in rats. We assessed the effects of MDMA [0.5, 2.5, 5, 10 and 15 mg/kg; intraperitoneally (I.P)] on spatial memory of male Wistar rats in the Morris water maze test (MWM) and brain mitochondrial function (i.e., reactive oxygen species, mitochondrial membrane potential, swelling and outer membrane damage, cytochrome c release, and ADP/ATP ratio). Concentrations of MDMA and its metabolite, MDA, were determined in plasma, cerebrospinal fluid (CSF) and brain which was obtained immediately after probe test of MWM (i.e., 4 h after last training trial). The results of this study indicate nonlinear kinetics of MDMA after I.P adminstration. Also, an insignificant correlation was observed between MDMA doses and the MDA/MDMA ratio in plasma, CSF, and brain. Moreover, the results showed that MDMA, but not MDA, accumulated in brain tissue by increasing the administered doses. Beside, MDMA-induced impairments of spatial memory and brain mitochondrial function were significantly correlated with the concentrations of both MDMA and MDA in plasma, CSF, and brain. Therefore, it can be suggested that MDMA and its metabolite, MDA, affect spatial memory and brain mitochondrial function.

Reduction of autophagy markers mediated protective effects of JNK inhibitor and bucladesine on memory deficit induced by Aß in rats.

Autophagy, the process of self-degradation of cellular components, has an important role in neurodegenerative diseases, such as Alzheimer's disease. In this study, we investigated the effects of SP600125 as c-Jun N-terminal kinase (JNK) inhibitor and bucladesine as a cyclic adenosine 3',5'-monophosphate (cAMP) analog on spatial memory and expression of autophagic factors in Aß-injected rats. Male Wistar rats were used. Rats were randomly allocated into five groups as following: amyloid beta (Aß)-only group, Aß + SP600125 (30 µg/1 µ/side, n = 7) and/or bucladesine (100 µM/1 µl/side, n = 7), and the normal control (vehicle only) group. The treatments were administered bilaterally to the CA1 sub-region of the hippocampus stereotaxically. Spatial reference memory was performed using Morris Water Maze 21 days later. The expression of authophagy markers (beclin1, Atg7, Atg12, and LC3 II/LC3 I) in the hippocampus was evaluated using western blotting. Compared to the vehicle group, Aß administration reduced spatial reference learning (P < 0.001) and memory (P < 0.01) and upregulated the expression of beclin1, Atg7, Atg12, and LC3 II/I (P < 0.0001). Compare to Aß-only group, the administration of SP600125 and/or bucladesine improved spatial reference learning (P < 0.001) and memory (P < 0.01). Compared to the Aß-only group, the treatment with SP600125 and/or bucladesine also reduced beclin1, Atg7, Atg12, and LC3 II/I (P < 0.0001) which was similar to amount of normal rats. In summary, it seems that the improvement of spatial memory by SP600125 and/or bucladesine in Aß-injected rats is in relation with normalizing of autophagy to the physiologic level, possibly through neuroprotection and/or neuroplasticity.