Parkinson’s Disease Brain Chemistry and Effect of Medicines

Chemical changes in the Brain

In Parkinson’s disease (PD) there is slow and progressive loss and deterioration of nerve cells of the brain especially those involved with regulation and control of movements. In a healthy person, an adequate amount of dopamine (a chemical messenger present in the body) is present in substantia nigra (an area of cluster of nerve cells in the brain). Normally, dopamine is carried by the nerve cells from this area to another cluster of nerve cells known as the corpus striatum where these nerves terminate.

Here, along with dopamine, the acetylcholine, (another chemical messenger), regulates the bodily movements. Complex chain of decisions which involves the interconnected groups of nerve cells commonly called as “ganglia” are responsible for the control of body movement. Information reaching the Striatum works with the substantia nigra and send impulses back and forth from the spinal cord to the brain. Two other regions of the brain which are responsible for a smooth movement in the body are called as basal ganglia and cerebellum.

In a patient with Parkinson’s disease there is an imbalance between the two chemical messengers dopamine and acetylcholine. In most of the cases, “there is loss of dopamine in the substantia nigra and degeneration of dopamine nerve terminals in the corpus striatum.”

Approximately 60-80% of dopaminergic neurons are lost (for reasons not yet understood) before the motor signs of Parkinson disease emerge. The motor signs of Parkinson’s disease involve  tremors, rigidity, muscular incoordination and weakness, frequent falls, and freezing of gait. Rarely, the hyperactivity of acetylcholine nerve cells may be the underlying cause of Parkinson’s disease. Another change observed in some cases is the presence of protein clusters known as “Lewy bodies” in the brain, which are characteristic, but not specific of PD. In other words the presence of lewy bodies is not unique to the Parkinson’s disease and these protein clumps have also been reported in various other neurological ailments.

At present, it is believed that PD is mainly caused by environmental factors and hereditary factors. A genetic predisposition (i.e. higher risk of disease if any close relative is suffering from PD) has been seen in the patients. There are very rare families where PD is inherited. Souten secondary formula of Parkinson’s disease are caused by ingestion of medicines such as Haloperidol (the drug used to treat hallucinations), reserpine (an important ingredient of some antihypertensive drugs), and metoclopramide  (an antiemetic).


Oxidative Stress in Parkinson’s Disease

The possible role of environmental risk factors associated with the development of disease include use of pesticides, consumption of contaminated well water, exposure to herbicides, and proximity to industrial plants or quarries. The most accepted theory establishing the link between these factors and degeneration in the brain is that of “oxidative stress”, which is hypothesized to play a very crucial role in the dopaminergic neurotoxicity. They predominantly contribute to the mitochondrial dysfunction, which is responsible in the generation of reactive oxygen species (ROS) to cause oxidative stress by causing a change in the electron transport chain of mitochondria, eventually leading to cell death. However it is only after the long term exposure of these substances to the body that the features of Parkinson’s disease are manifested.

The role of oxidative stress (increased levels of free radicals) in PD has been extensively studied. The utilization of energy in the brain can lead to increase in the concentration of free radicals (unstable highly reactive chemical compounds) e.g. hydrogen peroxide. In healthy individuals a balance is maintained between antioxidants and oxidative ions and thus oxidative stress does not occur. But in patients of PD, increased concentrations of free radicals and decreased levels of antioxidants have been observed which lead to nerve damage by lipid per-oxidation and pore formation in the cell membranes. The pore formation ultimately leads to the leakage of reactive oxygen species into the cell’s cytoplasm.

In addition to it, the failure of normal cellular process that occur in relation to the aging also contributes to the increased susceptibility of the dopaminergic neurons towards Parkinson’s disease. Parkinson’s disease itself is not fatal, however the serious complications associated with the disease make it the 14th top cause of death worldwide.

Drugs that Affect the Brain Chemistry in PD

The presently available treatments are symptomatic i.e. they treat the disease but do not alter the underlying degenerative process. These are helpful in restoring and maintaining function and quality of life for many years and are individualized as per the case. Symptoms of Parkinson’s disease arise because of the deficiency of dopamine in the brain so the treatment protocol must aim to restore the normal dopaminergic levels. Patients and Doctors work closely with the therapist throughout the course of the disease to analyse the brain chemistry of a Parkinson’s patient and to customise a suitable treatment program for their particular needs. However, some of the issues must be addressed before choosing the appropriate medication treatment, which includes the effectiveness of a specific drug group, loss of effectiveness with time, and its possible side effects. Most of the drugs accomplish the task by either :

  • Increasing the synthesis of dopamine (e.g. levodopa and carbidopa combination). It is considered to be the most effective drug to control the symptoms in all the phases of the disease and is better at improving the motor problems then other dopaminergic agonists. However, its effectiveness tends to reduce after 4 – 5 years of usage.
  • Enhance the action of dopamine (e.g. ropinirole, pramipexole)
  • Decrease the degradation process of dopamine (e.g. selegiline – selective inhibitor of MAO-B / Mono amine Oxidase B, an enzyme degrading dopamine)
  • Inhibitors (tolcapone and entacapone) of another degrading enzyme, COMT / catechol-O-methyl transferase
  • FDA has recently approved a drug called as rotigotine for the treatment of early and advanced cases of Parkinson’s disease. It is a common dopamine agonist drug and is delivered through a transdermal skin patch which is applied once a day.

The symptoms of PD in patients taking certain drugs especially antipsychotics like chlorpromazine can be treated by giving anticholinergic drugs like benztropine. The drugs which increase the dopamine levels are not helpful in these patients and the preventive role of antioxidants is still under study.

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