Investigation of tyrosine hydroxylase and BDNF in a low-dose rotenone model of Parkinson's disease

• Rotenone (2 mg/kg, 5 days/week, 4 weeks) was administered to rats by i.p. injections.
• TH levels remained unchanged in the substantia nigra, striatum or locus coeruleus.
• TH levels decreased in the olfactory bulb, but increased in the adrenal and colon.
• mBDNF levels were reduced in plasma but increased in the colon.
• This dosing paradigm may have potential to replicate early Parkinson's disease.

Tyrosine hydroxylase (TH, the rate limiting-enzyme in catecholamine synthesis) is regulated acutely via phosphorylation of 3 serine residues—Ser19, 31 and 40, and chronically via changes in TH protein levels. In this study, we aimed to investigate how TH is regulated in the brain, gut and adrenal gland as well as changes in mature brain-derived neurotrophic factor (mBDNF) and proBDNF levels in a low-dose (2 mg/kg, 5 days/week for 4 weeks) rotenone model of Parkinson's disease (PD). Rearing behaviour decreased by week 3 in the rotenone group (p < 0.01), with further decreases in rearing by week 4 (p < 0.001); however, TH remained unchanged in the substantia nigra (SN) and striatum; TH levels were also unaltered in other catecholaminergic cell groups of the brainstem such as A1C1 neurons or locus coeruleus. In the olfactory bulb, TH protein decreased (2.5-fold, p < 0.01) while Ser31 phosphorylation increased (1.4-fold, p < 0.05) in the rotenone group. In contrast, TH protein was increased in the adrenal gland (2-fold, p < 0.05) and colon (5-fold, p < 0.05) of rotenone rats. mBDNF levels were not changed in the SN but were significantly reduced in plasma and significantly increased in the colon (2-fold, p < 0.01) of rotenone-treated rats. This is the first study to assess TH and BDNF in the brain and periphery in the rotenone model before SN/striatum degeneration is evident. Together these results suggest that low-dose rotenone may have some potential to model the early stages of PD.