Lipid Oxidation Effect on Membrane Properties in Phosphatidylinositol- and Phosphatidylserine-Enriched Neuronal Biomimetic Models.

Dopaminergic medications have been a cornerstone in managing the symptoms of Parkinson's disease (PD), particularly motor symptoms such as bradykinesia, rigidity, and tremor. Levodopa (L-DOPA) is a precursor of dopamine (DA) that can cross the blood-brain barrier and replenish dopamine levels in the brain. In the 1960s, its introduction revolutionized the management of Parkinson's disease. L-DOPA provides significant short-term relief of symptoms, however, in the long term, complications such as motor fluctuations and L-DOPA-induced dyskinesias (LIDs) may appear. It became clear that there was an evident relationship between plasma L-DOPA levels and motor fluctuations. Therefore, methods to provide more stable plasma levels of L-DOPA were studied to smooth fluctuations (). Indeed, continuous intravenous infusion of L-DOPA was studied first. However, this method was limited by practicality and the risk of peripheral side effects. Then, continuous subcutaneous infusion of the DA agonist lisuride proved to significantly improve fluctuations. The same approach was then used with another potent DA agonist, apomorphine. The observation that not only L-DOPA but also DA agonists were able to overcome fluctuations suggested that a central continuous dopaminergic stimulation (CDS) was the main factor leading to the improvement of fluctuations and dyskinesias. Interestingly, apomorphine was given intravenously in a small group of patients who did not tolerate subcutaneous infusion, with dramatic reduction in OFF time and LIDs, proving that the more constant is the delivery of drug, the better is the control of complications. These experiments in advanced patients were followed by studies with oral DA agonists in early PD versus L-DOPA. All these studies showed that DA agonists in monotherapy induced significantly fewer fluctuations and LIDs. The most accredited explanation for these results was that DA agonists provided a more stable and continuous dopaminergic stimulation compared to oral L-DOPA because of their pharmacokinetic properties. In more recent years, and after years of studies for a jejunal formulation of L-DOPA, the development of a combination of L-DOPA and carbidopa intestinal gel (LCIG) formulation allowed for continuous delivery directly into the small intestine, ameliorating motor fluctuations and LIDs in advanced PD. It was also postulated that the reduction of the variability between L-DOPA concentrations independently from the total dose has a role in alleviating fluctuations and LIDs. Timeline of the therapeutic strategies implemented for the pursuit of continuous drug delivery (CDD). The four main classes of drugs employed for the symptomatic treatment of PD motor symptoms are represented. Continuous intravenous/subcutaneous administration or extended release (ER) formulations of direct dopaminergic agonists, along with continuous administration strategies of L-DOPA, represent the primary direct methods implemented to achieve stable plasmatic levels of dopaminergic active principles and thus CDD, aiming to achieve continuous dopaminergic stimulation (CDS) and smooth motor fluctuations. Simultaneously, the enzymatic inhibition strategy aims at the achievement of CDS by combining L-DOPA with monoamine oxidase type B inhibitors (MAOB-I), enabling the prolongation of L-DOPA half-life, and/or catechol-O-methyltransferase inhibitors (COMT-I), acting on the inhibition of L-DOPA main peripheral catabolic pathway, ensuring a higher bioavailability of dopamine in the central nervous system. The different drug classes are marked in different colors (COMT-I = green; MAOB-I = blue; L-DOPA formulations = yellow; DA agonists = red). The dates refer to the first published studies on each therapeutic strategy.