Dopamine Agonists in the Treatment of Parkinsons Disease-Past, Present and Future

Abstract

An attempt is made by the author to highlight the important events that laid the foundation of dopamine agonists as a treatment strategy for Parkinson s disease. This debilitating neurodegenerative disorder is long recognized as a result of progressive cell loss in the substantia nigra of the midbrain. The destruction of dopaminergic neurons with projections to the striatum results in the diminishing striatal dopamine levels. Anticholinergic drugs were once widely used to counteract the relative overactivity of cholinergic output from the basal ganglia and the strategy was only met with limited success. The discovery of dopamine depletion and the use of levodopa - a dopamine metabolic precursor, led the way to dopamine replacement therapy . The initial success with levodopa was soon overshadowed by the long-term side effects associated with levodopa. Many new drugs were developed with the hope to replace or strengthen the usefulness of levodopa. Apomorphine and ergot alkaloids have been around for some time; they are recently joined by newer dopamine agonists such as ropinirole and pramipexole. Each of these has its own characteristics and has occupied a place in the pharmacotherapy of Parkinson s disease. In this review older aporphines and ergot alkaloids are discussed first. More emphasis is directed to the side-effect profiles, metabolism and pharmacokinetics in terms of their unique chemical structures. The most recent agonists will be briefly discussed before we move on to the future - the future of emerging novel classes of promising dopaminergic agonists.

Unfolded annealing molecular dynamics conformers for wild-type and disease-associated variants of alpha-synuclein show no propensity for beta-sheetformation

“…It is possible that other factors not considered in our simulations, such as the presence of metal ions or excess of free monomeric protein, alter the conformational landscape of alpha-synuclein, perhaps favoring the formation of extended beta structures under these conditions. Experimental evidence [9,[33][34][35] exists for metal ions binding to alpha-synuclein that seems to support this hypothesis, and further simulations are necessary to investigate this possibility. Evidence also exists for modulation of alpha-synuclein conformation by other molecules such as dopamine derivatives [36] and pesticides [37][38][39][40], and a molecular docking-MD study is underway to investigate these effects.…”

“…Aggregation of the misfolded protein in the brain causes the formation of Lewy Bodies, dark colored masses in the brain, which are landmarks of PD [8]. The accumulation of alpha-synuclein in the brain results in loss of dopaminergic neurons, with consequent reduction of striatal dopamine levels [9]. These protein aggregates are toxic enough to cause damage to the part of the brain responsible for motor movements, which is physically translated as slower movement and tremors.…”

“…Drug treatments that are prescribed to PD patients in-cludes dopamine receptor agonists [9,[13][14][15][16], which alleviate symptoms but do not prevent progression of the disease. Currently, there is no drug treatment that specifically targets the aggregation of alpha-synuclein, or prohibits its accumulation.…”

Deranged NMDAergic cortico-subthalamic transmission underlies parkinsonian motor deficits

“…However, it is noted that striatal dopaminergic stimulation with D1R or D2R agonists, which presumably perturbs the balance between the direct and indirect pathways, fails to change MSN firing in mice (3) or locomotor behavior in rats (4). In this regard, it is interesting to note that the therapeutic effects of levodopa and dopamine agonists in PD are mainly investigated by systemic application (2,(5)(6)(7) rather than striatal infusion. Acute administration of dopamine antagonists rarely causes acute parkinsonism in humans (8) and fails to cause parkinsonian electrophysiological abnormalities in animals (9,10).…”

Genotoxic, neurotoxic and neuroprotective activities of apomorphine and its oxidized derivative 8-oxo-apomorphine

“…The oxidation-related properties of apomorphine lead to apparently paradoxical activities of the drug, which may act either as an antioxidant or as a prooxidant (reviewed in Ref. 21). Ubeda et al (22) reported that apomorphine can act as a pro-oxidant, leading to DNA damage and to deoxyribose degradation induced by Fe 3+ and Cu 2+ by a mechanism related to the generation of superoxide radicals.…”