Restoration of Mitochondrial Dysfunction in 6-Hydroxydopamine Induced Parkinson’s disease: a Complete Review

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by neuronal cell death in the specifi c brain region like basal ganglia, cerebral cortex and hippocampus. Symptoms associated with PD patients are rigidity, akathesia, tremor, postural imbalance, cognitive and memory dysfunctions. Pathological hallmarks are dopaminergic neuronal degeneration, neuro-infl ammation, oxidative stress, free radical generation. In the typical Parkinson's disease model, 6-Hydroxydopamine (6-OHDA) is delivered unilaterally by stereotactic injection into the SNc (substantia nigra pars-compacta) or the striatum mimics the PD symptoms. In addition, it has been shown that 6-OHDA is toxic to complex I & IV of the mitochondrial respiratory chain, leading to subsequent respiratory inhibition and further processed ATP depletion, oxidative stress and neuro-infl ammation. Forskolin (FSK), a diterpene natural plant phytochemical obtained from (Coleus Forskohli), a potent direct activator of adenyl cyclase (AC) enzyme which further activates cAMP/PK A /CREB pathway. FSK mediated activation of AC/cAMP/PK A / CREB pathway is responsible for various neuroprotective mechanisms Based on important and versatile role of FSK, the present study has been designed to investigate the role of cAMP mediated CREB activation in 6-hydroxydopamine induced mitochondrial associated neurotoxicity in rats. Further the studies are extended to understand the disease pathogenesis and to investigate and discuss the various possible central mechanisms involved in the effect of such targets using behavioral paradigm and biochemical markers of neurodegeneration.

Neuroprotective effect of solanesol against 3-nitropropionic acid-induced Huntington's disease-like behavioral, biochemical, and cellular alterations: Restoration of coenzyme-Q10-mediated mitochondrial dysfunction

“…[3] Mitochondrial dysfunctions are suggested to be involved in HD pathogenesis, which could be linked with direct interaction of mutant Htt with mitochondria ( mHtt ). [4] Evidence suggests that HD may be associated with impaired energy metabolism and inhibition of mitochondrial complexes (I, II, III, and IV) enzymes resulting in ROS production in striatal regions of HD brain. Mitochondrial dysfunction hypothesis explaining about the pathogenesis of HD was first tested pharmacologically using 3-nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase (SDH) which replicates most of the clinical and pathophysiological hallmarks of HD, such as spontaneous choreiform and dystonic movements, cognitive deficits including progressive degeneration of striatal tissue associated with loss of ATP depletion, oxidative–nitrosative stress, and excitotoxicity.…”

Divergent Effects of Haloperidol on Motor Versus Spatial Functions

“…Motor and non-motor defi cits have been reproduced in genetic models of Parkinson's disease [7], or after injections of neurotoxic agents that deplete dopamine concentrations in striatum [8]. Moreover, parkinsonian symptoms appear in schizophrenic subjects after high doses of dopamine-2 (D2) receptor antagonists such as chlorpromazine (CPZ) and haloperidol, to a lesser extent the more selective D4 receptor antagonist, clozapine [9].…”