Novel pharmacological strategies for motor complications in Parkinson’s disease

Abstract

In advanced Parkinson’s disease, the combination of disease progression and levodopa therapy leads to the development of motor problems complicating the therapeutic response, known as motor response complications. The nonphysiological, pulsatile stimulation produced by most currently available dopaminergic therapies triggers a complicated series of responses resulting in the dysregulation of glutamate receptors and many other neurotransmitter systems on striatal neurons. Although a number of novel compounds that provide a more continuous dopaminergic stimulation are becoming available, no practical way to accomplish this in a truly physiological manner currently exists. Novel strategies for pharmacological intervention with the use of nondopaminergic treatments, with drugs targeting selected transmitter receptors expressed on striatal neurons appear more promising. These include NMDA or AMPA antagonists, or drugs acting on 5-hydroxytryptamine subtype 2A, α2-adrenergic, adenosine A2A and cannabinoid CB1 receptors. Future strategies may also target pre- and postsynaptic components that regulate firing pattern, like synaptic vesicle proteins, or nonsynaptic gap junction communication mechanisms, or drugs with actions at the signal transduction systems that modulate the phosphorylation state of NMDA receptors. These new therapeutic strategies, alone or in combination, hold the promise of providing effective control or reversal of motor response complications.