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Daily rhythms of serotonin metabolism and the expression of clock genes in suprachiasmatic nucleus of rotenone-induced Parkinson’s disease male Wistar rat model and effect of melatonin administration

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Abstract

The circadian system in suprachiasmatic nucleus (SCN) involves regulated serotonin levels and coordinated expression of various clock genes. To understand circadian disfunction in the age-related neurodegenerative disorder Parkinson’s disease (PD), the rotenone-induced PD (RIPD) male Wistar rat model was used. The alterations in the rhythmic dynamic equilibrium of interactions between the various components of serotonin metabolism and the molecular clock were measured. There was significant decrease in the mean 24 h levels of tryptophan, 5-hydroxytryptophan (5-HTP), serotonin (5-HT), N-acetyl serotonin (NAS) and melatonin (MEL) by approximately 63, 51, 76 and 96 % respectively ( p ≤ 0.05). However significant increase in 5-methoxy indole acetic acid (5-MIAA), 5-methoxy tryptophol (5-MTOH), 5-hydroxy tryptophol (5-HTOH) indicated increased serotonin catabolism with the abolition of daily rhythms of MEL, 5-HTP and 5-MIAA in RIPD. 24 h mean levels of rPer1, rCry1, rBmal1 reduced by about 0.5, 0.74 and 0.39-fold and increased for rPer2 by about 1.7-fold. The daily pulse of rPer2, rCry1, rCry2 and rBmal1 significantly decreased by 0.36, 0.6, 0.14, 0.1 and 0.2-fold. As melatonin, an antioxidant and an endogenous synchronizer of rhythm declined in RIPD male Wistar rat model, the effects of melatonin-administration on the rhythmic expression of various clock genes were studied. Interestingly, melatonin-administration resulted in restoration of the phase of rPer1 daily rhythm in RIPD indicating differential sensitivity of various clock components towards melatonin. The animals which were administered both rotenone and MEL for 48 days interestingly showed neuroprotective effects in dark phase on correlations between expression of various genes.

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Acknowledgments

The work is supported by DBT Grant (BT/PR3974/MED/30/813/2012) and ICMR (Ref. No. BMS/NTF/14/2006–2007), DST Nano (Ref: 8:18) Grant to AJ. UM is thankful to DBT for fellowship.

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  1. Neurobiology and Molecular Chronobiology Laboratory, Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India

    Ushodaya Mattam & Anita Jagota

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  1. Ushodaya Mattam
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Correspondence to Anita Jagota.

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10522_2014_9541_MOESM1_ESM.pdf

Supplementary material 1 (PDF 10 kb). Fig. S1 Effect of rotenone-treatment on body weight in Group 1B (PBS/Sham), Group 1C (Vehicle/V) and Group 1D (rotenone-induced Parkinson’s disease/RIPD rat model). Each value is mean ± SEM (n = 10), p ≤ 0.05 * refers to comparison with vehicle

10522_2014_9541_MOESM2_ESM.pdf

Supplementary material 2 (PDF 251 kb). Fig S2. Tyrosin hydroxylase (TH) and α- Synuclein immunoreactivity in Rat Substantia nigra (SN). A (i and ii) TH immunoblot and densitometry analysis. B (i and ii) α- Synuclein immunoblot and densitometry analysis. Lane 1: Protein molecular weight marker, lane 2 and 3: PBS/Sham, lane 4 and 5: Vehicle/V and lane 6, 7 and 8:Rotenone-induced Parkinson’s disease/RIPD. C. TH-immunoreactivity (TH-ir) in coronal SN brain sections of Group 1C (Vehicle/V) and Group 1D (RIPD). (i) bar = 1 mm (ii) bar = 200 μm SNpC- Substantia nigra pars compacta, SNpR- Substantia nigra pars reticulata. Data were expressed as mean ± SEM. P ≤ 0.05, * - refers to comparison with vehicle. Rotenone-treated rats showed significant decrease in TH-immunoreactivity by about 0.32 fold, p ≤ 0.001 and increase in α-Synuclein- immunoreactivity by about 1.65 fold, p ≤ 0.005, compared to vehicle group

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Mattam, U., Jagota, A. Daily rhythms of serotonin metabolism and the expression of clock genes in suprachiasmatic nucleus of rotenone-induced Parkinson’s disease male Wistar rat model and effect of melatonin administration. Biogerontology 16, 109–123 (2015). https://doi.org/10.1007/s10522-014-9541-0

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