Exploring the aetiology and treatment of hyposmia in a rat model of pre-motor Parkinson's disease

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The symptomatology of Parkinsons disease (PD) consists of motor and non-motor
symptoms (NMSs). The latter has been linked to a loss of neurotransmitters other than
dopamine and it has been shown to be modulated by treatments that do not act directly
on the dopaminergic system, such as the glucagon-like peptide-1 receptor agonist
exendin-4 (EX-4). Nevertheless, the aetiology of NMs, alongside with their potential
treatments, has yet to be fully investigated. Recently, using injections of the
neurotoxins N--N-ethyl-2-bromobenzylamine (DSP-4) and 6-hydroxydopamine (6-
OHDA), we developed a rat model of pre-motor PD that displays NMSs in the absence
of motor symptoms. Taking advantage of this model, the effect of partial noradrenergic
and dopaminergic denervation in several brain regions within the olfactory pathway
was investigated using immunohistochemical and electrophysiological techniques.
Neuroinflammation was observed in the primary olfactory cortex, and the combined
denervation led to a reduction in the expression of interneuronal calcium binding
proteins in both the primary olfactory cortex and the prefrontal cortex. On the contrary,
calcium binding proteins expression in the olfactory bulbs was found to be increased,
alongside with dopaminergic expression. Electrophysiologically, neurones recorded
intracellularly in layer II-III of the primary olfactory cortex from the model exhibited
abnormal prolonged epileptiform-like depolarizing postsynaptic potentials on local
electrical stimulation of lateral olfactory tract (LOT) afferent fibers. Both structural and
electrophysiological changes were partially prevented following treatment with EX-4.
This rat model of pre-motor PD offers a useful means for research into early diagnosis
as well as early intervention of PD, possibly resulting in a delay of disease progression
together with improved patients quality life.

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