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Cited by (33)
Current Status, Gaps, and Weaknesses of the Mechanism of Selective Dopaminergic Toxicity of MPTP/MPP<sup>+</sup>
2017, Advances in Molecular ToxicologyCitation Excerpt :Thus, the selective uptake through DAT followed by the inhibition of mitochondrial electron transport chain complex I, could be responsible for the selective dopaminergic toxicity of N-MeβC derivatives, similarly to MPP+. As mentioned above, the salient features of the currently accepted mechanism of the selective dopaminergic toxicity of MPTP/MPP+ include (Fig. 3.1): (a) lipophilic MPTP readily crosses the blood–brain barrier and enter the brain [171]; (b) in the brain, MPTP enters the astrocytes and MAO-B in these cells convert it to its oxidized product, MPP+ [75–78]; (c) MPP+ is released to the extracellular space from astrocytes specifically through OCT-3 in the glial membrane [79]; (d) extracellular MPP+ is effectively taken up into dopaminergic neurons through DAT [80,81]; (e) inside dopaminergic neurons, MPP+ actively accumulates in the mitochondria to millimolar levels (based on studies with isolated mitochondria 5–20 mM) and inhibit the complex I of the electron transport chain [88,89]; (f) complex I inhibition leads to ATP depletion, mitochondrial membrane depolarization [89], and increased ROS production causing the apoptotic cell death [90–95]; (g) MPP+ in dopaminergic cells also actively accumulates in synaptic vesicles through VMAT2 limiting its availability for mitochondrial entry and complex I inhibition; and (h) synaptic vesicle accumulation of MPP+ is considered to be an effective in vivo detoxification mechanism (Fig. 3.1) [100,102–105]. It should also be noted that the most critical aspects of the dopaminergic toxicity of endogenous TIQs, TβCs as well as the other toxins are also explained based on the currently accepted mechanism of the selective dopaminergic toxicity of MPTP/MPP+ [80,159,169].
Apparent opposite effects of tetrabenazine and reserpine on the toxic effects of 1-methyl-4-phenylpyridinium or 6-hydroxydopamine on nigro-striatal dopaminergic neurons
2003, Brain ResearchCitation Excerpt :Reinhard Jr. et al. [31] have observed that a treatment with TBZ, 30 min before MPTP i.p. injection, potentiates the neurotoxicity undergone by mice. The discrepancy between the results of Naudin et al. [28], Reinhard Jr. et al. [31] and ours, may be explained by the time course of the TBZ side effects, such as hypothermia, and that a delay of 30 min between administration of TBZ and the toxin is insufficient to obtain a marked inhibition of the VMAT2. Reinhard Jr. et al. [31] have performed an i.p. injection of MPTP 30 min after TBZ injection.
L-DOPA does not cause neurotoxicity in VMAT2 heterozygote knockout mice
2002, NeuroToxicologyMethamphetamine neurotoxicity: Necrotic and apoptotic mechanisms and relevance to human abuse and treatment
2001, Brain Research Reviews