Neuroprotection in Parkinson's Disease
Neuroprotection in Parkinson's Disease
Parkinson's disease (PD) is a common neurodegenerative movement disorder that is associated with significant medical disability, reduction in quality of life, and, in advanced stages, caregiver burden. Approximately 0.5-1.0 million individuals in the United States have been diagnosed with PD, most falling within the age range of 55 to 60 years at time of diagnosis. With the growth of the senior population in the United States, the prevalence of PD is expected to increase. In response to this anticipated increase in the prevalence of PD, the search for agents that may delay or arrest its pathologic progression (ie, neuroprotective agents) has become a high priority among researchers. Neuroprotection is defined as protecting neurons from cellular damage induced by various biochemical insults associated with the pathogenesis of PD. Therefore, in order to understand the complexity of identifying a neuroprotective agent, an overview of the pathology and pathophysiology of PD and the myriad of putative biochemical mechanisms that may result in neuronal damage is warranted.
Mark Ruscin, PharmD, Associate Professor, University of Colorado Health Sciences Center, Denver, discussed this topic in his presentation, "Neuroprotection and New Treatments for Parkinson's Disease," at the American College of Clinical Pharmacy 2003 Annual Meeting in Atlanta, Georgia.
Classically, the biochemical defect in PD has been described as an imbalance between dopamine and acetylcholine. In PD, it is estimated that motor symptoms do not appear until a critical reduction of 80% in striatal dopamine concentration has occurred. In the normal state, there is a balance between the excitatory effects of acetylcholine and the inhibitory effects of dopamine within the extrapyramidal motor system. But as the nigrostriatal degeneration progresses, a state of dopamine depletion and cholinergic excess occurs. Additionally, imbalances of other neurotransmitters (eg, gamma-amino-butyric acid, glutamate, norepinephrine, serotonin) and neuronal degeneration within other subcortical structures such as the locus ceruleus and hypothalamus are also characteristic of PD.
The profound reduction in striatal dopamine disrupts the complex motor circuit loop of the extrapyramidal motor system that is composed of the basal ganglia (striatum and globus pallidus) and the substantia nigra. Within the substantia nigra, dopamine is synthesized, stored, and transported to the striatum. Striatal neurons then communicate with neurons of the thalamocortical pathway (subthalamic nucleus, the thalamus, and the cerebral cortex) through complex series of stimulatory and inhibitory neural pathways. In PD, the end result of striatal dopamine depletion is the expression of aberrant motor movement.
The cardinal motor features of PD are tremor, muscular rigidity, bradykinesia (ie, slowness of movement), and postural instability. These physical findings, in isolation, are rather nonspecific, but as a whole, they constitute "parkinsonism." Stooped posture and freezing are 2 additional characteristic physical features of PD. Mental symptoms are also common and include anxiety and depression. Hallucinations and delusions are also common in the advanced stages of PD and are usually induced by the current anti-PD drugs.
Parkinson's disease (PD) is a common neurodegenerative movement disorder that is associated with significant medical disability, reduction in quality of life, and, in advanced stages, caregiver burden. Approximately 0.5-1.0 million individuals in the United States have been diagnosed with PD, most falling within the age range of 55 to 60 years at time of diagnosis. With the growth of the senior population in the United States, the prevalence of PD is expected to increase. In response to this anticipated increase in the prevalence of PD, the search for agents that may delay or arrest its pathologic progression (ie, neuroprotective agents) has become a high priority among researchers. Neuroprotection is defined as protecting neurons from cellular damage induced by various biochemical insults associated with the pathogenesis of PD. Therefore, in order to understand the complexity of identifying a neuroprotective agent, an overview of the pathology and pathophysiology of PD and the myriad of putative biochemical mechanisms that may result in neuronal damage is warranted.
Mark Ruscin, PharmD, Associate Professor, University of Colorado Health Sciences Center, Denver, discussed this topic in his presentation, "Neuroprotection and New Treatments for Parkinson's Disease," at the American College of Clinical Pharmacy 2003 Annual Meeting in Atlanta, Georgia.
Classically, the biochemical defect in PD has been described as an imbalance between dopamine and acetylcholine. In PD, it is estimated that motor symptoms do not appear until a critical reduction of 80% in striatal dopamine concentration has occurred. In the normal state, there is a balance between the excitatory effects of acetylcholine and the inhibitory effects of dopamine within the extrapyramidal motor system. But as the nigrostriatal degeneration progresses, a state of dopamine depletion and cholinergic excess occurs. Additionally, imbalances of other neurotransmitters (eg, gamma-amino-butyric acid, glutamate, norepinephrine, serotonin) and neuronal degeneration within other subcortical structures such as the locus ceruleus and hypothalamus are also characteristic of PD.
The profound reduction in striatal dopamine disrupts the complex motor circuit loop of the extrapyramidal motor system that is composed of the basal ganglia (striatum and globus pallidus) and the substantia nigra. Within the substantia nigra, dopamine is synthesized, stored, and transported to the striatum. Striatal neurons then communicate with neurons of the thalamocortical pathway (subthalamic nucleus, the thalamus, and the cerebral cortex) through complex series of stimulatory and inhibitory neural pathways. In PD, the end result of striatal dopamine depletion is the expression of aberrant motor movement.
The cardinal motor features of PD are tremor, muscular rigidity, bradykinesia (ie, slowness of movement), and postural instability. These physical findings, in isolation, are rather nonspecific, but as a whole, they constitute "parkinsonism." Stooped posture and freezing are 2 additional characteristic physical features of PD. Mental symptoms are also common and include anxiety and depression. Hallucinations and delusions are also common in the advanced stages of PD and are usually induced by the current anti-PD drugs.
Source...