Ratos espontaneamente hipertensos (SHR) são resistentes a um modelo animal progressivo da doença de Parkinson: um estudo neuroquímico e comportamental

Abstract

Parkinson’s disease (PD) is an aging-related progressive neurodegenerative disorder characterized by motor and non-motor symptoms, which affects 1-2% of the world population above 60 years old. In Brazil, this approximately 600 thousand people live with this disorder. Thus, PD is an important burden to countries with increasing life expectancy. The epidemiology of PD highlight intrinsic and extrinsic risk factors that are stochastic to the development of the disorder. Predisposing genetic factors comprise punctual mutations and polymorphisms with functional significance, while exposition to toxins is emphasizedas environmental factors. Nevertheless, few animal studies focus on the investigation of the interaction between these factors. Such may be accomplished by comparing the effects of substances that cause parkinsonism on rat strains with different genetic backgrounds. Recently, the repeated treatment with a low-dose of reserpine – an irreversible inhibitor of the vesicular monoamine transporter (VMAT2) – was suggested as a progressive model of PD. Rats under this treatment regimen show progressive catalepsy behavior, oral dyskinesia and spontaneous motor activity decrement. In parallel, compared to Wistar rats, SHR (Spontaneously Hypertensive Rat) are resistant to acute reserpine-induced oral dyskinesia. In view of these findings, we aimed to assess whether SHR would be resistant to repeated reserpine-induced motor and neurochemical deficits when submitted to the progressive model of PD. Thus, we submitted Wistar and SHR rats to the acute (1 mg/kg) or repeated (0,1 mg/kg, 15x, every other day) treatment with reserpine and investigated the progression of motor deficits in the catalepsy bar, oral dyskinesia, and spontaneous activity on the open field. Our results revealed that, for both treatment regimens, SHR rats were resistant to the motor impairment for all motor parameters assessed. Moreover, these differences were detected for both the latency to instauration and the magnitude of the impairment. The alterations were concomitant to a decrement in the optical density of tyrosine hydroxylase and an increment in α-synuclein immunostaining by immunohistochemistryin the nigro-striatal pathway of both strains submitted to reserpine treatment. These neurochemical alterations resulted from reserpine treatment also reflected in the levels of monoamines – dopamine and serotonin – in the nigro-striatal pathway of these animals. Altogether, similarly to the motor behavior, SHR rats displayed lower magnitude and a delay to monoamine depletion. In conclusion, the current results clearly evidence the resilience of SHR to the repeated low-dose reserpine protocol. These findings uncover new potential underlying neurochemical, molecular and genetic differences in the SHR strain relevant to the study of susceptibility to PD.