Parkinson's disease (PD), characterized by selective midbrain nigrostriatal dopaminergic degeneration, is consistently associated with moderate systemic mitochondrial dysfunction. Downstream degeneration of spinal cord has also been suggested in PD, although the mechanisms have not been much investigated. In the present study, two mitochondrial toxicants, 1-methyl-4-phenylpyridinium ion (MPP+) and rotenone were tested in ventral spinal cord (VSC 4.1) motoneuronal cells. Cell death was assessed by morphological and biochemical means to discern a lower apoptosis-inducing concentration and LC50, which were subsequently compared in further cytoprotection experiments. Mitochondrial toxicants dose-dependently induced increase in intracellular free Ca2+ level, which was conducive for increased expression and activities of Ca2+-activated neutral protease calpain and downstream caspase-3. Thus, mitochondrial damage triggered apoptotic mechanisms in spinal cord motoneurons. Inhibition of calpain by calpeptin significantly attenuated damaging effects of MPP+ and rotenone on motoneurons, especially at low apoptosis-inducing concentrations of toxicants and partly at their LC50, as demonstrated by absence of DNA ladder formation and decrease in TUNEL-positive cells. Cytoprotection by calpeptin was observed with marked decreases in Bax:Bcl-2 ratio and activities of calpain and caspase-3, which affirmed the role of mitochondrial dysfunction and involvement of intrinsic pathway in mediation of apoptosis. These findings strongly suggested that parkinsonian toxicants MPP+ and rotenone at low doses induced cascade of cell damaging effects in spinal cord motoneurons, thus, highlighting the possibility of induction of apoptotic mechanisms in these cells, when subjected to mitochondrial stress. Cytoprotection rendered by calpeptin further validated the involvement of calpain in apoptosis and suggested calpain inhibition as a potential neuroprotective strategy.
Sporadic Parkinson’s disease (PD) is now interpreted as a complex nervous system disorder in which the projection neurons are predominantly damaged. Such an interpretation is based on mapping of Lewy body (LB) and Lewy neurite (LN) pathology. Symptoms of the human disease are much widespread, which span from preclinical nonmotor symptoms and clinical motor symptoms to cognitive discrepancies often seen in advanced stages. Existing symptomatic treatments further complicate with overt drug-irresponsive symptoms. PD is better understood by assimilation of extranigral degenerative pathways with nigrostriatal degenerative mechanisms. The term ‘extranigral’ appeared first in ‘90s’ to more rigorously define the nigral pathology by process of elimination. However, as clinicians progressively identified PD symptoms unresponsive to the gold standard drug L-DOPA, definitions of PD symptoms were redefined. Nonmotor symptoms prodromal to motor symptoms just as preclinical to clinical, and conjointly emerged the concept of nigral versus extranigral degeneration in PD. While nigrostriatal degeneration is responsible for the neurobiological substrates of extrapyramydal motor features, extranigral degeneration corroborates a vast majority of other changes in discrete central, peripheral, and enteric nervous system nuclei which together account for global symptoms of the human disease. As an extranigral site, spinal cord has also been implicated in PD progression. Interconnected to the upper central nervous system structures with descending and ascending pathways, spinal neurons participate in movement and sensory circuits, controlling movement and reflexes. Several clinical and in vivo studies have demonstrated signs of parkinsonism-related degenerative processes in spinal cord, which led to recent consideration of spinal cord as an area of potential therapeutic applications. In nutshell, the review explores how the existing animal models can actually reflect the human disease in order to facilitate PD research. Evolution of extranigral degeneration studies has been succinctly revisited, followed by a survey on animal models in light of recent findings in clinical PD. Together, it may help to develop effective therapeutic strategies.
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