Nicotine suppresses Parkinson’s disease like phenotypes induced by Synphilin-1 overexpression in Drosophila melanogaster by increasing tyrosine hydroxylase and dopamine levels

Abstract

It has been observed that there is a lower Parkinson’s disease (PD) incidence in tobacco users. Nicotine is a cholinergic agonist and is the principal psychoactive compound in tobacco linked to cigarette addiction. Different studies have shown that nicotine has beneficial effects on sporadic and genetic models of PD. In this work we evaluate nicotine’s protective effect in a Drosophila melanogaster model for PD where Synphilin-1 (Sph-1) is expressed in dopaminergic neurons. Nicotine has a moderate effect on dopaminergic neuron survival that becomes more evident as flies age. Nicotine is beneficial on fly survival and motility increasing tyrosine hydroxylase and dopamine levels, suggesting that cholinergic agonists may promote survival and metabolic function of the dopaminergic neurons that express Sph-1. The Sph-1 expressing fly is a good model for the study of early-onset phenotypes such as olfaction loss one of the main non-motor symptom related to PD. Our data suggest that nicotine is an interesting therapeutic molecule whose properties should be explored in future research on the phenotypic modulators of the disease and for the development of new treatments.

CREB1K292 and HINFPK330 as Putative Common Therapeutic Targets in Alzheimer’s and Parkinson’s Disease

“…For instance, Esteves et al, 2017, demonstrated that nicotine effectively prevented prefrontal long-term potentiation and memory deficits induced by streptozotocin in AD, 53 whereas Carvajal-Oliveros et al, 2021, demonstrated that nicotine suppresses the PD-like phenotype induced by synphilin-1 overexpression through increased dopamine levels. 54 Similarly, a study concluded that the balance between dopamine and adenosine signals regulates the PKA/Rap1 pathway in spiny neurons, where D1R and A2AR agonist enhanced PKA-mediated Rap1 phosphorylation in vivo and in vitro . 55 Further, studies demonstrated that impaired GnRH production is directly linked to oxidative stress and mitochondrial dysfunction in neurons.…”

“…Gap junction (TUBB4B), GnRH signaling pathway (CDC42), and Rap1 signaling pathway (CDC42 and FGFR1) were critical pathways in which HUB proteins were involved and may be potential biological pathway targets for the AD and PD crosstalk. For instance, Esteves et al, 2017, demonstrated that nicotine effectively prevented prefrontal long-term potentiation and memory deficits induced by streptozotocin in AD, whereas Carvajal-Oliveros et al, 2021, demonstrated that nicotine suppresses the PD-like phenotype induced by synphilin-1 overexpression through increased dopamine levels . Similarly, a study concluded that the balance between dopamine and adenosine signals regulates the PKA/Rap1 pathway in spiny neurons, where D1R and A2AR agonist enhanced PKA-mediated Rap1 phosphorylation in vivo and in vitro .…”

Nicotine Has a Therapeutic Window of Effectiveness in a Drosophila melanogaster Model of Parkinson’s Disease

“…Indeed, previous research in our laboratory showed that when heterozygous park 25 flies were treated with nicotine, they demonstrated improvements in climbing, flight, lifespan, and olfaction [13]. More recently, nicotine treatment in another Drosophila PD model also suppressed PD-like phenotypes [20].…”

“…Mutation of the Drosophila ortholog of the PRKN gene, parkin (park), leads to a tenable model of PD that has many similarities to PD patients: selective loss of dopaminergic neurons, decreased motor function, loss of olfaction, reduced lifespan, mitochondrial dysfunction, and others [13][14][15][16][17]. Another use of Drosophila PD models has been to identify potential therapeutics for PD, including, but not limited to, nicotine, acteoside, gastrodin, and other nutraceuticals [13,[18][19][20][21].…”

Nutrition and Gut–Brain Pathways Impacting the Onset of Parkinson’s Disease

“…However, this result was observed only among smokers [ 134 ]. Indeed, some studies have found that smoking is associated with a reduced risk of developing PD as tobacco may regulate striatal activity through the dopaminergic system [ 135 , 136 ]. Thus, evidence linking vitamin B6 with the risk of developing PD should be interpreted with caution.…”