The rat rotenone model reproduces the abnormal pattern of central catecholamine metabolism found in Parkinson's disease

Abstract

Background: Recent reports indicate that Parkinson's disease (PD) involves specific functional abnormalities in residual neurons—decreased vesicular sequestration of cytoplasmic catecholamines via the vesicular monoamine transporter (VMAT) and decreased aldehyde dehydrogenase (ALDH) activity. This double hit builds up the autotoxic metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), the focus of the catecholaldehyde hypothesis for the pathogenesis of PD. An animal model is needed that reproduces this abnormal catecholamine neurochemical pattern. Methods: Adult rats received subcutaneous vehicle or rotenone (2 mg/kg/day via a minipump) for 10 days. Locomotor activity was recorded and striatal tissue sampled for catechol contents and catechol ratios that indicate the above abnormalities. Results: Compared to vehicle, rotenone reduced locomotor activity (p=0.002), decreased tissue dopamine concentrations (p=0.00001), reduced indices of vesicular sequestration (3,4-dihydroxyphenylacetic acid (DOPAC)/dopamine) and ALDH activity (DOPAC/DOPAL) (p=0.0025, p=0.036), and increased DOPAL levels (p=0.04). Conclusions: The rat rotenone model involves functional abnormalities in catecholaminergic neurons that replicate the pattern found in PD putamen. These include a vesicular storage defect, decreased ALDH activity, and DOPAL buildup. The rat rotenone model provides a suitable in vivo platform for studying the catecholaldehyde hypothesis.

Cardiac noradrenergic deficiency revealed by 18F-dopamine positron emission tomography identifies preclinical central Lewy body diseases

“…A vesicular storage defect would not only deplete releasable neurotransmitter stores but also promote autotoxicity from augmented oxidation of cytoplasmic catecholamines ( 37 – 39 ). Diminished vesicular storage in existing nerve terminals could have any of several causes, such as decreased mitochondrial complex 1 activity ( 40 ), α-synuclein (αS) oligomers ( 37 , 41 ), or decreased VMAT2 availability ( 42 ), all of which are potential therapeutic targets; however, no previous study has determined whether indices of attenuated vesicular sequestration in cardiac sympathetic nerves precede central LBDs in at-risk individuals.…”

Mitochondrial Toxicant-Induced Neuronal Apoptosis in Parkinson’s Disease: What We Know so Far

“…In vivo experimental model shows RO induces loss of dopaminergic neurons in the substantia nigra, one of the characteristic features of PD neuropathology. 86 Rotenone also replicates the clinical features of PD, including the aggregation of α-synuclein and the formation of Lewy bodies. 87 …”

Assessing the Neurotoxicity of a Sub-Optimal Dose of Rotenone in Zebrafish (Danio rerio) and the Possible Neuroactive Potential of Valproic Acid, Combination of Levodopa and Carbidopa, and Lactic Acid Bacteria Strains

“…One of the most eloquent examples of the effect of ROT on the level of DA is provided by the studies of Alam and Schmidt [ 61 ] and Biehlmaier et al [ 62 ]. Intraperitoneal (ip) injection with 1.5 mg/kg, 2 mg/kg/day, and 2.5 mg/kg between ten days and two months induce degeneration of dopaminergic neurons [ 63 ] in the posterior part of the striatum, the prefrontal cortex (PFC), and SN. A deletion in the Ndufs4 gene impacts the complex I activity in mesencephalic neurons but does not affect survival [ 64 ].…”