Some More About PARKINSON’S DISEASE (PD)

This article is an extension of my previous article which was about Parkinson’s disease. The outflow of the striatum proceeds along two distinct routes, termed the direct and indirect pathways. The direct pathway is formed by neurons in the striatum that project directly to the output stages of the basal ganglia, the substantial nigra pars reticulata (SNpr) and the globus pallidus interna (GPi); these, in turn, relay to the ventroanterior and ventrolateral thalamus, which provides excitatory input to the cortex.

The neurotransmitter of both links of the direct pathway is g-aminobutyric acid (GABA), which is inhibitory, so that the net effect of stimulation of the direct pathway at the level of the striatum is to increase the excitatory outflow from the thalamus to the cortex. The indirect pathway is composed of striate neurons that project to the globus pallidus externa (GPe). This structure, in turn, innervates the sub thalamic nucleus (STN), which provides outflow to the SNpr and GPi output stage.

As in the direct pathway, the first two links the projections from striatum to GPe and GPe to STN¾use the inhibitory transmitter GABA; however, the final link the projection from STN to SNpr and GPi is an excitatory glutamatergic pathway. Thus the net effect of stimulating the indirect pathway at the level of the striatum is to reduce the excitatory outflow from the thalamus to the cerebral cortex.

The key feature of this model of basal ganglia function, which accounts for the symptoms observed in PD as a result of loss of dopaminergic neurons, is the differential effect of dopamine on the direct and indirect pathways. The dopaminergic neurons of the substantia nigra pars compacta (SNpc) innervate all parts of the striatum; however, the target striatal neurons express distinct types of dopamine receptors. The striatal neurons giving rise to the direct pathway express primarily the excitatory D1 dopamine receptor protein, whereas the striatal neurons forming the indirect pathway express primarily the inhibitory D2 type.

Thus dopamine released in the striatum tends to increase the activity of the direct pathway and reduce the activity of the indirect pathway, whereas the depletion that occurs in PD has the opposite effect. The net effect of the reduced dopaminergic input in PD is to increase markedly the inhibitory outflow from the SNpr and GPi to the thalamus and reduce excitation of the motor cortex. There are several limitations of this model of basal ganglia function. In particular, recent work has shown that the anatomical connections are considerably more complex than envisioned originally. In addition, many of the pathways involved I PD, use not just one but several neurotransmitters. For example, the neuropeptides substance P and dynorphin are found predominantly in striatal neurons making up the direct pathway, whereas most of the indirect pathway neurons express encephalin.

These transmitters are expected to have slow modulator effects on signalling, in contrast to the rapid effects of glutamate and GABA, but the functional significance of these modulator effects remains unclear. Nevertheless, the model is useful and has important implications for the rational design and use of pharmacological agents in PD. First, it suggests that to restore the balance of the system through stimulation of dopamine receptors, the complementary effect of actions at both D1 and D2 receptors, as well as the possibility of adverse effects that may be mediated by D3, D4, or D5 receptors, must be considered. Second, it explains why replacement of dopamine is not the only approach to the treatment of PD. Drugs that inhibit cholinergic receptors have long been used for treatment of Parkinsonism.

Although their mechanisms of action are not completely understood, it seems likely that their effect is mediated at the level of the striatal projection neurons, which normally receive cholinergic input from striatal cholinergic interneuron. Few clinically useful drugs for Parkinsonism are presently available based on actions through GABA and glutamate receptors, even though both have crucial roles in the circuitry of the basal ganglia. However, they represent a promising avenue for drug development.

Sever drugs are used either alone or in combination like levodopa and carbidopa are employed to manage epilepsy; some of them are levodopa, carbidopa, catechol-O Methyl transferees inhibitors such as tolcapone and entacapone, dopamine receptor agonists such as rpinirole, selective monoamine oxidase inhibitors such as selegiline, muscarinic receptor antagonists such as benztropine and diphenhydramine, amantadine and some neuroprotective agents are also used to manage Parkinson’s disease.

By: Ammarah Khan

    

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