Many of the motoric features that define
Parkinson's disease (PD) result primarily from the loss of dopaminergic neurons of the substantia nigra.
l-dopa remains at present the most powerful symptomatic drug for the treatment of this condition. However, motor complications of chronic
l-dopa treatment have emerged as a major limitation of this
therapy. Slowing or delaying the progression of the disease with neuroprotective
therapies may delay the need for
l-dopa. In the past few years, novel insight into the pathogenetic mechanisms of neurodegeneration in PD has been provided. Mitochondrial function deficiency, increased oxidative stress, apoptosis, excitotoxicity, and
inflammation are part of the processes that ultimately result in neurodegeneration. Drugs that are now under clinical scrutiny as
neuroprotectant include molecules that combine one or more of the following properties: (1)
monoamine oxidase inhibition (
rasagiline,
safinamide); (2) mitochondrial enhancement (
coenzyme Q10,
creatine); (3) antiapoptotic activity; (4) anti-inflammatory activity; (5)
protein aggregation inhibition; (6) neurotrophic activity. In advanced
Parkinson's disease, the combination of
disease progression and
l-dopa therapy leads to the development of motor response complications, particularly wearing off, on off,
dyskinesias and dystonias. The nonphysiologic pulsatile stimulation of striatal
dopamine receptors, produced by the currently available
dopaminergic drugs, may trigger a dysregulation of many
neurotransmitter systems within the basal ganglia, mainly localized on medium spiny striatal neurons. These include alterations of glutamatergic, serotonergic,
adrenergic and
adenosine A(2A) receptors. Novel strategies for pharmacological intervention with nondopaminergic treatments hold the promise of providing effective control or reversal of motor response complications. Of particular interest are
NMDA and
AMPA antagonists or drugs acting on
5-HT subtype 2A, alpha2-adrenergic, and
adenosine A(2) receptors. Future strategies may also target pre- and postsynaptic components that regulate firing pattern of basal ganglia neurons, such as synaptic vesicle
proteins, nonsynaptic gap junction communication mechanisms, or signal transduction systems that modulate the phosphorylation state of glutamatergic receptors.