Symptoms
As mentioned in an earlier post, signs of Parkinson's Disease (PD) include resting tremor, bradykinesia, impaired postural reflexes and "cogwheel rigidity" (jerky movements when the muscle is passively stretched). Its onset is usually asymmetrical (i.e. one side of the body is affected before the other). Another diagnostic criterion for Parkinson's is responsiveness to levodopa, the dopamine precursor used as a treatment.
Pathology
Some of the pathological changes present in PD include the presence of Lewy bodies, dystrophic Lewy neurites, and loss of dopamine neurons in the substantia nigra. (Wikipedia tells me that Lewy bodies are abnormal aggregates of protein.) Lewy bodies and Lewy neurites form from the deposition of abnormal α-synuclein. Lewy bodies are not unique to PD, however: they occur in other disorders, and even healthy seniors may have them.
The neuronal pathways behind PD are a bit more complicated, especially since none of us have any neuroscience background. The lecturer's explanations made absolutely zero sense to me, so here's what I learned from Rang and Dale's Pharmacology:
First, let's talk about the extrapyramidal nervous system. There are several different components to this system, such as the substantia nigra (which is made up of the pars compact and pars reticulata), the corpus striatum, globus pallidus, subthalamic nucleus, thalamaus, and motor cortex. Dopaminergic neurons travel from the pars compacta (of the substantia nigra) to the corpus striatum, where they can have excitatory effects on GABAergic neurons going to the pars reticulata (also of the substantia nigra) or inhibitory effects on GABAergic neurons going to the globus pallidus.
First, I'm going to discuss the pars reticulata. GABAergic neurons are mostly inhibitory, so activation of the GABAergic neuron travelling from the corpus striatum to pars reticulata causes inhibition of the next neurons, which are GABAergic neurons going to the thalamus. Now, inhibiting an inhibitory neuron (disinhibition) causes activation, so glutamatergic (excitatory) neurons in the thalamus become activated. These neurons go to the motor cortex, stimulating movement.
But what about the other pathway? Inhibition of GABAergic neurons to the globus pallidus causes activation of the GABAergic neurons there. These GABAergic neurons go to the subthalamic nucleus, causing inhibition of glutamatergic neurons travelling to the pars reticulata. This also inhibits the GABAergic neurons travelling from the pars reticulata to the thalamus, thus removing the brakes on the glutamatergic neurons travelling to the motor cortex.
In Parkinson's Disease, the dopaminergic pathway between the pars compacta and corpus striatum is impaired in some way. This means that there is no disinhibition of GABAergic neurons travelling from the pars reticulata to the thalamus, which in turn means that the glutamatergic neurons to the motor cortex are inhibited (hence bradykinesia and difficulty in initiating movement).
Sorry if all of that was confusing. Here's a diagram from Rang and Dale's Pharmacology, Eighth Edition (p. 492), which might help you to visualise it all better:
Genetics
Most patients with PD (~95%) have sporadic PD, but the remaining 5% may have an inherited genetic disorder responsible for PD. Possible genes involved include α-syn, Parkin, DJ-1 and Pink-1.
MPTP, 6-OHDA, and Parkinson's
As discussed here, MPTP can damage dopaminergic neurons in a fairly roundabout manner. Therefore, it is often used to create animal models of Parkinson's. It has been found that you need to lose at least 80% of dopaminergic neurons in order to develop Parkinson's, which fits with Seeman's hypothesis stating that antagonising over 80% of dopaminergic neurons causes extrapyramidal side effects.
6-OHDA (6-hydroxydopamine) is another toxin that can destroy dopaminergic neurons. Interestingly enough, giving different drugs to 6-OHDA lesioned rats can make them turn in different directions. Giving amphetamine (which increases dopamine release) to these rats causes ipsiversive turning (i.e. towards the side of the lesion). Giving a direct D1 or D2 receptor agonist causes contraversive turning. (Unfortunately, I don't really understand why.)
Sinemet
Sinemet is a combination of L-DOPA (a dopamine precursor) and carbidopa (a peripherally selective aromatic L-amino acid decarboxylase inhibitor). Carbidopa blocks peripheral synthesis of dopamine so that high enough levels of L-DOPA can cross the blood-brain barrier. L-DOPA, being a precursor for dopamine, increases the production of dopamine. Sinemet is the gold-standard treatment for PD.
One of the problems with Sinemet is that it displays fluctuations in efficacy. This occurs for several reasons: firstly, it has a short half-life and secondly, after meals amino acids compete for transport across the blood-brain barrier, so meals can reduce the amount of L-DOPA getting into the brain. One of the other problems with Sinemet is that, being a dopamine agonist, it comes with a risk of psychosis.
Another problem with Sinemet is that it can result in the development of dyskinesia, called L-DOPA induced dyskinesia (LiD). It is still uncertain as to what causes LiD. Some people believe that LiD may be due to the pulsatile, rather than continuous, delivery of Sinemet. Therefore pumps and other methods of administration are being trialled. Others believe that LiD may be due to dopamine release by serotonergic neurons. L-DOPA may be taken up by serotonergic neurons, and since serotonergic neurons also have aromatic L-amino acid decarboxylase, they may also begin producing dopamine. Release of dopamine without feedback control may be responsible for dyskinesias.
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