Melatonin reduces the neuronal loss, downregulation of dopamine transporter, and upregulation of D2 receptor in rotenone‐induced parkinsonian rats

Abstract

Parkinson's disease (PD) is a movement disorder resulting from nigrostriatal dopaminergic neurodegeneration. The impairment of mitochondrial function and dopamine synaptic transmission are involved in the pathogenesis of PD. Two mitochondrial inhibitors, 1-methyl-4-phenylpyridine (MPP(+)) and rotenone, have been used to induce dopaminergic neuronal death both in in vitro and in vivo models of PD. Because the uptake of MPP(+) is mediated by the dopamine transporter (DAT), we used a cell-permeable rotenone-induced PD model to investigate the role of DAT and dopamine D2 receptor (D2R) on dopaminergic neuronal loss. Rotenone subcutaneously infused for 14 days induced PD symptoms in rats, as indicated by reduced spontaneous locomotor activity (hypokinesis), loss of tyrosine hydroxylase (TH, a marker enzyme for dopamine neurons) immunoreactivity in the substantia nigra and striatum, obvious alpha-synuclein accumulation, downregulated DAT protein expression, and upregulated D2R expression. Interestingly, rotenone also caused significant noradrenergic neuronal loss in the locus coeruleus. Melatonin, an antioxidant, prevented nigrostriatal neurodegeneration and alpha-synuclein aggregation without affecting the rotenone-induced weight loss and hypokinesis. However, rotenone-induced hypokinesis was markedly reversed by the DAT antagonist nomifensine and body weight loss was attenuated by the D2R antagonist sulpiride. In addition, both antagonists significantly prevented the reduction of striatal TH or DAT immunoreactivity but not the loss of nigral TH- and DAT-immunopositive neurons. These results suggested that oxidative stress and DAT downregulation are involved in the rotenone-induced pathogenesis of nigrostriatal dopaminergic neurodegeneration, whereas D2R upregulation may simply represent a compensatory response.

Neuroprotection in Parkinson's Disease: A Systematic Review of the Preclinical Data

“…The authors also measured higher activity of SOD and catalase in the brain when melatonin was administered. These results were supported by another rotenone study in which rats chronically exposed to rotenone were protected by co-treatment with melatonin [115]. In the same year, Capitelli et al, [98] conducted an MPTP test in rats.…”

A review of sleep disorders and melatonin

“…Several studies demonstrated melatonin treatment prevents dopamine-producing neuronal loss and dopamine transporter down-regulation in a rotenone model of PD [40]. Hendaus et al demonstrated that melatonin plays a role in neuroprotection in a phenylhydrazine hydrochloride (PHZ)-induced perinatal hypoxic-ishcemic encephalopathy model in rats.…”

Melatonin as a Neuroprotective Agent in the Rodent Models of Parkinson’s Disease: Is it All Set to Irrefutable Clinical Translation?

“…Melatonin prevents the nigrostriatal neurodegeneration and alpha-synuclein aggregation [72] induced by rotenone. Melatonin scavenges rotenone-induced hydroxyl radicals and restores the decreased glutathione level and changes in the catalytic activities of superoxide and catalase in the substantia nigra [74].…”

“…Rotenone leads to the dopaminergic neurodegeneration and reduces the number of TH-positive neurons of the nigrostriatal pathway. Although degeneration caused by rotenone is non-specific in nature, it is the only neurotoxin which exhibits well-defined Lewy body formation and aggregation of alpha-synuclein along with depletion of glutathione, disruption of axonal transport, and onset of several critical histological, biochemical, and pathological hallmarks of sporadic PD [23,27,72]. Since rotenone does not rely on the dopamine transporter uptake to exert neurotoxicity, therefore, it could be considered as an ideal model to assess neuroprotection [73].…”

“…As PD is mainly an aging-related disease characterized by an increased oxidative stress and reduced or altered expression of antioxidant, anti-inflammatory, toxicant metabolizing, apoptotic, and energy metabolism-related genes, and melatonin possesses the potent anti-oxidant, free-radical scavenging, anti-apoptotic, and anti-inflammatory properties, therefore it can effectively encounter the altered expression of several genes and proteins Table 1 Summary of a few studies showing the major effects of melatonin against chemicals-induced cellular and animal PD models Inhibits neuroinflammation and protects the dopaminergic neurons by restoring complex I activity, reduces microglial activation, apomorphine-induced rotations, oxidative stress and attenuates apoptosis [7,[30][31][32] MPTP Inhibits the mitochondrial complex I and causes selective, however, mainly acute degeneration of dopaminergic neurons and does not form distinct Lewy body Inhibits neuroinflammation and 6-OHDA production, protects the dopaminergic neurons by reducing TH-positive cell loss and hypolocomotion, restores mitochondrial complex I activity, decreases microglial activation, attenuates mitochondrial DNA damage, prevents dysfunction of glutathione system, blocks caspase-3 activation, protects the nigrostriatum from oxidative stress, and reduces oxidative stress and lipid peroxidation [14,41,[44][45][46][47][48][49][51][52][53] Rotenone Inhibits complex I of the electron transport chain, non-selectively degenerates the dopaminergic neurons, induces acute neurodegeneration and causes Lewy body formation Prevents the nigrostriatal neurodegeneration and alpha-synuclein aggregation, reduces glutathione depletion and catalase activity, increases SOD activity, protects the mitochondria from oxidative stress, and increases cell viability [72,74,76] Maneb and paraquat Inhibit complex I and III and degenerate the dopaminergic neurons Protects the dopaminergic neurons and inhibits the expression of pro-apoptotic genes [8] Methamphetamine/ amphetamine Degenerates the dopaminergic neurons and reduces dopamine packaging in synaptic vesicles…”