Abstract
A pharmacological and genetic blockade of the dopamine D3 receptor (D3R) has shown to be neuroprotective in models of Parkinson’s disease (PD). The anxiolytic drug buspirone, a serotonin receptor 1A agonist, also functions as a potent D3R antagonist. To test if buspirone elicited neuroprotective activities, C57BL/6 mice were subjected to rotenone treatment (10mg/kg i.p for 21 days) to induce PD-like pathology and were co-treated with increasing dosages of buspirone (1, 3, or 10 mg/kg i.p.) to determine if the drug could prevent rotenone-induced damage to the central nervous system (CNS). We found that high dosages of buspirone prevented the behavioural deficits caused by rotenone in the open field test. Molecular and histological analyses confirmed that 10 mg/kg of buspirone prevented the degeneration of TH-positive neurons. Buspirone attenuated the induction of interleukin-1β and interleukin-6 expression by rotenone, and this was paralleled by the upregulation of arginase-1, brain-derived neurotrophic factor (BDNF), and activity-dependent neuroprotective protein (ADNP) in the midbrain, striatum, prefrontal cortex, amygdala, and hippocampus. Buspirone treatment also improved mitochondrial function and antioxidant activities. Lastly, the drug prevented the disruptions in the expression of two neuroprotective peptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP). These results pinpoint the neuroprotective efficacy of buspirone against rotenone toxicity, suggesting its potential use as a therapeutic agent in neurodegenerative and neuroinflammatory diseases, such as PD.
Highlights
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterised by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and resulting in a deficit of dopamine (DA) in the striatum [1]
It was shown that neuroinflammation alone is sufficient to promote the death of dopaminergic neurons, as shown in a study involving an injection of the inflammatory mimetic, LPS, into the rodent brain, which resulted in increased levels of inflammatory mediators prior to the loss of dopaminergic neurons [8]
Buspirone is clinically used as an anxiolytic and has been previously utilised as a positive control in the assessment of the exploratory behaviour of C57BL/6 mice in the open field (OF) [20] (Supplementary Figure S1)
Summary
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterised by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and resulting in a deficit of dopamine (DA) in the striatum [1]. The environmental toxin, rotenone, is a popular PD-mimetic due to its ability to reproduce the major clinical and behavioural features of PD in rodents, including motor deficits, dopaminergic degeneration, mitochondrial impairment, and neuroinflammation [4,5]. It is a major contributor to PD pathology and is consistently linked to disease progression and clinical severity [8]. It was shown that neuroinflammation alone is sufficient to promote the death of dopaminergic neurons, as shown in a study involving an injection of the inflammatory mimetic, LPS, into the rodent brain, which resulted in increased levels of inflammatory mediators prior to the loss of dopaminergic neurons [8]. Adding complexity to PD pathogenesis is the discovery that DA itself can control inflammation [9]
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