Abstract
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of Lewy bodies and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpC). MPTP is widely used to generate murine PD model. In addition to classical motor disorders, PD patients usually have non-motor symptoms related to autonomic impairment, which precedes decades before the motor dysfunction. This study's objective is to examine the effects of MPTP on noradrenergic neurons in the hindbrain, thereby on the cardiovascular function in mice. Adult mice received 10 mg/kg/day of MPTP (4 consecutive days) to generate PD model. Systolic blood pressure was measured by tail cuff system in conscious mice, and baroreflex sensitivity was evaluated by heart rate alteration in response to a transient increase or decrease in blood pressure induced by intravenous infusion of phenylalanine (PE) or sodium nitroprusside (SNP) in anesthetized condition, respectively. Baseline heart rate and heart rate variability were analyzed in both sham and MPTP-treated mice. Dopamine, norepinephrine, and related metabolites in the plasma and brain tissues including SNpC, locus coeruleus (LC), rostroventrolateral medulla (RVLM), and nucleus tractus solitarii (NTS) were measured by liquid chromatography-mass spectrometry (LC-MS). Tyrosine hydroxylase-positive (TH+) neurons in above nuclei were quantified by immunoreactivities. We found that in addition to the loss of TH+ neurons in SNpC, MPTP treatment induced a dramatic reduction of TH+ cell counts in the LC, RVLM, and NTS. These are associated with significant decreases of dopamine, norepinephrine, and epinephrine in above nuclei. Meanwhile, MPTP induced a lasting effect of baroreflex desensitization, tachycardia, and decreased heart rate variability compared to the sham mice. Notably, MPTP treatment elevated sympathetic outflow and suppressed parasympathetic tonicity according to the heart rate power spectrum analysis. Our results indicate that the loss of TH+ neurons in the brainstem by MPTP treatment led to impaired autonomic cardiovascular function. These results suggest that MPTP treatment can be used to study the autonomic dysfunction in murine model.