Tracking extranigral degeneration in animal models of Parkinson’s disease: quest for effective therapeutic strategies

Abstract

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.

Mitochondria-targeted antioxidants for treatment of Parkinson's disease: Preclinical and clinical outcomes

“…PD is also associated with the presence of ubiquitin- and α-synuclein-positive cytoplasmic inclusions known as Lewy bodies within surviving dopaminergic neurons [6]. In addition to the nigrostriatal dopaminergic defects, emerging clinical evidence suggests that extranigral degeneration and non-motor symptoms are key features of early stages of PD pathogenesis [7-10]. …”

Critical role of calpain in spinal cord degeneration in Parkinson's disease

“…Conjoint lines of evidence from clinical reports and experimental studies have suggested degeneration of spinal cord in PD as outlined in recent reviews (Knaryan et al . ; Vivacqua et al . ).…”

Sensory neuropathy and nociception in rodent models of Parkinson's disease

“…Similar alterations occur in rodent motor neurons in genetic and toxin-induced PD models (described in detail below). These were associated with signs of muscle dystrophy (Knaryan et al, 2011; Lee et al, 2002; Samantaray et al, 2008; Vivacqua et al, 2009), but the pathology of somatosensory neurons of the dorsal root ganglia or trigeminal ganglia has not been studied in rodents.…”