Spontaneously Hypertensive Rats (SHR) Are Resistant to a Reserpine-Induced Progressive Model of Parkinson’s Disease: Differences in Motor Behavior, Tyrosine Hydroxylase and α-Synuclein Expression

Abstract

Reserpine is an irreversible inhibitor of vesicular monoamine transporter-2 (VMAT2) used to study Parkinson’s disease (PD) and screening for antiparkinsonian treatments in rodents. Recently, the repeated treatment with a low-dose of reserpine was proposed as a progressive model of PD. Rats under this treatment show progressive catalepsy behavior, oral movements and spontaneous motor activity decrement. In parallel, compared to Wistar rats, spontaneously hypertensive rats (SHR) are resistant to acute reserpine-induced oral dyskinesia. We aimed to assess whether SHR would present differential susceptibility to repeated reserpine-induced deficits in the progressive model of PD. Male Wistar and SHR rats were administered 15 subcutaneously (s.c.) injections of reserpine (0.1 mg/kg) or vehicle, every other day and motor activity was assessed by the catalepsy, oral movements and open field tests. Only reserpine-treated Wistar rats presented increased latency to step down in the catalepsy test and impaired spontaneous activity in the open field. On the other hand, there was an increase in oral movements in both reserpine-treated strains, although with reduced magnitude and latency to instauration in SHR. After a 15-day withdrawn period, both strains recovered from motor impairment, but SHR animals expressed reduced latencies to reach control levels. Finally, we performed immunohistochemistry for tyrosine hydroxylase (TH) and α-synuclein (α-syn) 48 h after the last injection or 15 days after withdrawn. Reserpine-treated animals presented a reduction in TH and an increase in α-syn immunoreactivity in the substantia nigra and dorsal striatum (dSTR), which were both recovered after 15 days of withdraw. Furthermore, SHR rats were resistant to reserpine-induced TH decrement in the substantia nigra, and presented reduced immunoreactivity to α-syn in the dSTR relative to Wistar rats, irrespective of treatment. This effect was accompanied by increase of malondaldhyde (MDA) in the striatum of reserpine-treated Wistar rats, while SHR presented reduced MDA in both control and reserpine conditions relative to Wistar strain. In conclusion, the current results show that SHR are resilient to motor and neurochemical impairments induced by the repeated low-dose reserpine protocol. These findings indicate that the neurochemical, molecular and genetic differences in the SHR strain are potential relevant targets to the study of susceptibility to PD.

Female Rats Are Resistant to Cognitive, Motor and Dopaminergic Deficits in the Reserpine-Induced Progressive Model of Parkinson’s Disease

“…Corroborating previous studies, we observed that reserpine treatment induced a progressive motor impairment in male rats ( Fernandes et al, 2012 ; Santos et al, 2013 ; Leão et al, 2017 ; Lins et al, 2018 ; Bispo et al, 2019 ). Interestingly, male rats showed more susceptibility to these motor alterations than female rats.…”

“…Nevertheless, Restreated rats, irrespective of sex, presented a significant decrease in motor activity 48 h after the 10th and 15th injections. In this regard, other studies have described similar effects for males (Santos et al, 2013;Leão et al, 2017;Lins et al, 2018;Bispo et al, 2019) and females (Bispo et al, 2019). Although there is a visually more pronounced reduction in locomotion in reserpine females than in males in the second open field session, statistical analysis did not show a significant interaction between time (repeated sessions) and sex.…”

“…Besides the lower susceptibility to increased catalepsy, female rats were not susceptible to the oral dyskinesia (evaluated by the vacuous chewing movements) induced by repeated treatment with a low dose of reserpine, which was present in males. Previous studies shown increased VCM response in males with the same protocol used here (Fernandes et al, 2012;Peres et al, 2016;Leão et al, 2017). However, one prior study reported increased reserpine-induced VCM response in female mice (Silva et al, 2002) after an acute injection of 1.0 mg/kg reserpine.…”

“…In this work, we investigated sex differences in motor, cognitive and neurochemical alterations at different stages of repeated low-dose reserpine administration, a progressive animal model of PD ( Santos et al, 2013 ; Leão et al, 2015 , 2017 ; Peres et al, 2016 ; Campelo et al, 2017 ; Lins et al, 2018 ; Bispo et al, 2019 ).…”

“…The repeated low-dose reserpine protocol has been used as a model of progressive parkinsonism, showing phenomenological (progressive motor alterations) and construct (reduced dopaminergic parameters, increased oxidative stress, and augmented alpha-synuclein expression) similarities with PD ( Fernandes et al, 2012 ; Santos et al, 2013 ; Leão et al, 2015 , 2017 , 2021 ; Ikram and Haleem, 2019 ). Unlike neurotoxin models, which lead to acute severe motor impairment, the low-dose repeated reserpine protocol allows the observation of progressive motor impairments as well as premotor deficits such as cognitive prejudice, anxiety and nociception alterations ( Santos et al, 2013 ; Leal et al, 2019 ; Cintra et al, 2021 ; Dos Santos et al, 2021 ).…”