Structural Changes Observed in the Piriform Cortex in a Rat Model of Pre-motor Parkinson’s Disease

Abstract

Early diagnosis of Parkinson’s disease (PD) offers perhaps, the most promising route to a successful clinical intervention, and the use of an animal model exhibiting symptoms comparable to those observed in PD patients in the early stage of the disease, may facilitate screening of novel therapies for delaying the onset of more debilitating motor and behavioral abnormalities. In this study, a rat model of pre-motor PD was used to study the etiology of hyposmia, a non-motor symptom linked to the early stage of the disease when the motor symptoms have yet to be experienced. The study focussed on determining the effect of a partial reduction of both dopamine and noradrenaline levels on the olfactory cortex. Neuroinflammation and striking structural changes were observed in the model. These changes were prevented by treatment with a neuroprotective drug, a glucagon-like peptide-1 (GLP1) receptor agonist, exendin-4 (EX-4).

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

“…Deimination has hitherto not been assessed in pre-motor PD and was therefore the subject of our current study as such post-translationally mediated changes may result in early onset pro-inflammatory and neurodegenerative processes and therefore offer an opportunity for early intervention. Interestingly, in the current study using a rat model of pre-motor PD, that has been shown to display non motor symptoms in the absence of motor dysfunction and neuroinflammation [32], an increase in deiminated proteins was observed in the brain vasculature, particularly in the cortex and hippocampus. Such elevated F95 positive detection observed here correlates somewhat with a previous study on human PD post-mortem brain tissue, although that study reported elevation of deiminated proteins in the substantia nigra [10].…”

“…Rats were divided into two experimental groups: sham-treated animals (n = 3) and toxin-treated model (pre-motor model-n = 3). This pre-motor PD model was shown to present non-motor symptoms in the absence of motor dysfunction in a previous study [32]. The pre-motor PD models did not present any motor dysfunction prior to culling.…”

“…A hitherto unrecognised contribution of deiminated proteins to the inflammatory responses, which previously have been shown in the pre-motor PD rat model [32], has to also be considered via the release of deiminated neuronal proteins from necrotic neurons, as well as via the circulation of deiminated proteins in the cerebrospinal fluid, which can contribute to progressive pathology due to generation of autoantibodies [117]. Furthermore, the significant increase observed in F95-positive brain vasculature of the pre-motor PD model, in particular in the cortex and hippocampus, and to some extent in the white matter, may also affect both local and systemic EV release and contribute to the spread and progression of pathology.…”

“…Recent work has emphasised the association of selected microRNAs to PD [27,122,123] and roles for microRNAs in neuroinflammation have received increased attention [25,124]. As neuroinflammation is thought to be a facilitator of PD pathogenesis, and was observed in the pre-motor PD model used in this study [32,125], we assessed changes in relative expression levels of three inflammatory and hypoxia associated microRNAs: miR21, miR155, and miR210. These microRNAs have previously been related to neurodegenerative diseases, including PD, although none of these microRNA (miRs) have been assessed, or associated with, pre-motor PD before the current study.…”

“…Male Sprague-Dawley rats (200-250 g-Charles River Laboratories, U.K.) were kept under constant conditions of humidity (40-60%), temperature (18-22 • C), and a 12 h light-dark cycle. The induction of the pre-motor model was carried out as previously described [32]. In brief, intraperitoneal administration of either N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, Sigma-Aldrich; a noradrenergic neurotoxin-pre-motor model) at a dose of 25 mg/kg, or sterile saline (sham animals) was performed 4 days prior to dopaminergic neurotoxin insult with 6-hydroxydopamine (6-OHDA).…”