Neuroscience
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Comparative Study
Ampakines reduce methamphetamine-driven rotation and activate neocortex in a regionally selective fashion.
It has been proposed that glutamatergic and dopaminergic systems are functionally opposed in their regulation of striatal output. The present study tested the effects of drugs that enhance AMPA-receptor-mediated glutamatergic transmission (ampakines) for their effects on dopamine-related alterations in cortical activity and locomotor behavior. Rats with unilateral 6-hydroxydopamine lesions of the ascending nigro-striatal dopamine system were sensitized to methamphetamine and then tested for methamphetamine-induced circling behavior in the presence and absence of ampakines CX546 and CX614. ⋯ Still larger ampakine-elicited effects were obtained in parietal cortex of the dopamine-depleted hemisphere where labeling densities were increased by approximately 60% above values found in methamphetamine-alone rats. With these effects, the hemispheric asymmetry of cortical activation was less pronounced in the ampakine-cotreatment group as compared with the methamphetamine-alone group. These results indicate that positive modulation of AMPA-type glutamate receptors 1) can offset behavioral disturbances arising from sensitized dopamine receptors and 2) increases aggregate neuronal activity in a regionally selective manner that is probably dependent upon behavioral demands.
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Comparative Study
The mitochondrial complex I inhibitor annonacin is toxic to mesencephalic dopaminergic neurons by impairment of energy metabolism.
The death of dopaminergic neurons induced by systemic administration of mitochondrial respiratory chain complex I inhibitors such as 1-methyl-4-phenylpyridinium (MPP(+); given as the prodrug 1-methyl-1,2,3,6-tetrahydropyridine) or the pesticide rotenone have raised the question as to whether this family of compounds are the cause of some forms of Parkinsonism. We have examined the neurotoxic potential of another complex I inhibitor, annonacin, the major acetogenin of Annona muricata (soursop), a tropical plant suspected to be the cause of an atypical form of Parkinson disease in the French West Indies (Guadeloupe). When added to mesencephalic cultures for 24 h, annonacin was much more potent than MPP(+) (effective concentration [EC(50)]=0.018 versus 1.9 microM) and as effective as rotenone (EC(50)=0.034 microM) in killing dopaminergic neurons. ⋯ Attempts to restore oxidative phosphorylation with lactate or pyruvate failed to provide protection to dopaminergic neurons whereas idoacetate, an inhibitor of glycolysis, inhibited the survival promoting effects of glucose and mannose indicating that these two hexoses acted independently of mitochondria by stimulating glycolysis. In conclusion, our study demonstrates that annonacin promotes dopaminergic neuronal death by impairment of energy production. It also underlines the need to address its possible role in the etiology of some atypical forms of Parkinsonism in Guadeloupe.
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Comparative Study
Androgens modulate neuronal vulnerability to kainate lesion.
Testosterone has been shown to have multiple beneficial effects on neuronal viability in developing and adult animals. Most often, testosterone promotes neural health indirectly via enzymatic conversion to estradiol by aromatase. Unclear is whether androgens can directly modulate vulnerability to neuronal insults in adult animals. ⋯ The depletion of endogenous androgens by GDX significantly augmented lesion severity, consistent with the hypothesis that androgens are involved in maintaining cell viability. Importantly, DHT hormone replacement in GDX rats significantly attenuated kainate-induced neuron loss in CA2/3, suggesting direct androgen neuroprotection. These results demonstrate that androgens act as endogenous modulators of neuron viability, a function that may be compromised in aging men as a consequence of normal, age-related androgen depletion.
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We have conducted studies to determine the potential of dietary factors to affect the capacity of the brain to compensate for insult. Rats were fed with a high-fat sucrose (HFS) diet, a popularly consumed diet in industrialized western societies, for 4 weeks before a mild fluid percussion injury (FPI) or sham surgery was performed. FPI impaired spatial learning capacity in the Morris water maze, and these effects were aggravated by previous exposure of the rats to the action of the HFS diet. ⋯ The combination of FPI and the HFS diet had more dramatic effects on the active state (phosphorylated) of synapsin I and CREB. There were no signs of neurodegeneration in the hippocampus of any rat group assessed with Fluoro-Jade B staining. The results suggest that FPI and diet impose a risk factor to the molecular machinery in charge of maintaining neuronal function under homeostatic and challenging situations.
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Numerous studies have investigated the expression of various cytokine families in the CNS after brain injury. The gp130 or interleukin (IL)-6-type cytokines have received a great deal of focus, and it is clear that they exhibit an acute and robust upregulation in various brain injury models. We are interested to determine, however, whether endogenously expressed cytokines in the CNS act in a direct neuromodulatory manner. ⋯ SOCS-2 displayed a relatively higher level of basal expression, particularly in CA3, and a mild and transient downregulation by 24 h. These findings corroborate the hypothesis that seizure-induced gp130 cytokines play a direct neuromodulatory role in the hippocampus. Since in our previous study we did not detect cytokine receptor expression in non-principal cells, it is unclear what elicits SOCS-3 expression in this population.