Low Concentrations of Methamphetamine Can Protect Dopaminergic Cells against a Larger Oxidative Stress Injury: Mechanistic Study

Mild stress can protect against a larger insult, a phenomenon termed preconditioning or tolerance. To determine if a low intensity stressor could also protect cells against intense oxidative stress in a model of dopamine deficiency associated with Parkinson disease, we used methamphetamine to provide a mild, preconditioning stress, 6-hydroxydopamine (6-OHDA) as a source of potentially toxic oxidative stress, and MN9D cells as a model of dopamine neurons. We observed that prior exposure to subtoxic concentrations of methamphetamine protected these cells against 6-OHDA toxicity, whereas higher concentrations of methamphetamine exacerbated it. The protection by methamphetamine was accompanied by decreased uptake of both [3H] dopamine and 6-OHDA into the cells, which may have accounted for some of the apparent protection. However, a number of other effects of methamphetamine exposure suggest that the drug also affected basic cellular survival mechanisms. First, although methamphetamine preconditioning decreased basal pERK1/2 and pAkt levels, it enhanced the 6-OHDA-induced increase in these phosphokinases. Second, the apparent increase in pERK1/2 activity was accompanied by increased pMEK1/2 levels and decreased activity of protein phosphatase 2. Third, methamphetamine upregulated the pro-survival protein Bcl-2. Our results suggest that exposure to low concentrations of methamphetamine cause a number of changes in dopamine cells, some of which result in a decrease in their vulnerability to subsequent oxidative stress. These observations may provide insights into the development of new therapies for prevention or treatment of PD

Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a Prion-Like Disorder?

Altered protein handling is thought to play a key role in the etiopathogenesis of Parkinson's disease (PD), as the disorder is characterized neuropathologically by the accumulation of intraneuronal protein aggregates (Lewy bodies and Lewy neurites). Attention has particularly focused on the alpha-synuclein protein, as it is the principal component of Lewy pathology. Moreover, point mutations in the alpha-synuclein gene cause rare familial forms of PD. Importantly, duplication/triplication of the wild type alpha-synuclein gene also cause a form of PD, indicating that increased levels of the normal alpha-synuclein protein is sufficient to cause the disease. Further, single nucleotide polymorphisms in the alpha-synuclein gene are associated with an increased risk of developing sporadic PD. Recent evidence now suggests the possibility that alpha-synuclein is a prion-like protein and that PD is a prion-like disease. Within cells, alpha-synuclein normally adopts an alpha-helical conformation. However, under certain circumstances, the protein can undergo a profound conformational transition to a beta-sheet-rich structure that polymerizes to form toxic oligomers and amyloid plaques. Recent autopsy studies of patients with advanced PD who received transplantation of fetal nigral mesencephalic cells more than a decade earlier demonstrated that typical Lewy pathology had developed within grafted neurons. This suggests that alpha-synuclein in an aberrantly folded, beta-sheet-rich form had migrated from affected to unaffected neurons. Laboratory studies confirm that alpha-synuclein can transfer from affected to unaffected nerve cells, where it appears that the misfolded protein can act as a template to promote misfolding of host alpha-synuclein. This leads to the formation of larger aggregates, neuronal dysfunction, and neurodegeneration. Indeed, recent reports demonstrate that a single intracerebral inoculation of misfolded alpha-synuclein can induce Lewy-like pathology in cells that can spread from affected to unaffected regions and can induce neurodegeneration with motor disturbances in both transgenic and normal mice. Further, inoculates derived from the brains of elderly alpha-synuclein-overexpressing transgenic mice have now been shown to accelerate the disease process when injected into the brains of young transgenic animals. Collectively, these findings support the hypothesis that alpha-synuclein is a prion-like protein that can adopt a self-propagating conformation that causes neurodegeneration. We propose that this mechanism plays an important role in the development of PD and provides novel targets for candidate neuroprotective therapies. (C) 2013 Movement Disorder Societ

Manifestações neurologicas do hiperparatireoidismo: estudo de 120 casos

É feito um estudo retrospectivo de 120 pacientes internados para investigação de hiperparatireoidismo. Tendo em vista as manifestações neurológicas do hiperparatireoidismo primário realizamos também um confronto com os achados de outros autores

Activation of phosphoinositide 3-kinase by D2 receptor prevents apoptosis in dopaminergic cell lines.

Whereas dopamine agonists are known to provide symptomatic benefits for Parkinson's disease, recent clinical trials suggest that they might also be neuroprotective. Laboratory studies demonstrate that dopamine agonists can provide neuroprotective effects in a number of model systems, but the role of receptor-mediated signalling in these effects is controversial. We find that dopamine agonists have robust, concentration-dependent anti-apoptotic activity in PC12 cells that stably express human D(2L) receptors from cell death due to H(2)O(2) or trophic withdrawal and that the protective effects are abolished in the presence of D(2)-receptor antagonists. D(2) agonists are also neuroprotective in the nigral dopamine cell line SN4741, which express endogenous D(2) receptors, whereas no anti-apoptotic activity is observed in native PC12 cells, which do not express detectable D(2) receptors. Notably, the agonists studied differ in their relative efficacy to mediate anti-apoptotic effects and in their capacity to stimulate [(35)S]guanosine 5'-[gamma-thio]triphosphate ([(35)S]GTP[S]) binding, an indicator of G-protein activation. Studies with inhibitors of phosphoinositide 3-kinase (PI 3-kinase), extracellular-signal-regulated kinase or p38 mitogen-activated protein kinase indicate that the PI 3-kinase pathway is required for D(2) receptor-mediated cell survival. These studies indicate that certain dopamine agonists can complex with D(2) receptors to preferentially transactivate neuroprotective signalling pathways and to mediate increased cell survival

Levodopa-induced dyskinesias in the absence of nigrostriatal degeneration

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