Oxygen is essential for animal life, but oxidative processes within nerve cells and oxidative events caused by certain environmental substances might lead to dopamine cell loss and the eventual signs of Parkinson's disease.

It had been shown that the inactivation of dopamine by a process of oxidation resulted in the formation of hydrogen peroxide and other free radicals. Such free radicals were capable of cellular damage. It could be argued that whatever the toxic substance that triggered the production of free radicals, it was the oxidative mechanisms that predisposed some people to the loss of dopamine cells.

Second it was known that a pigmented chemical called lipofuscin tended to show up in greater proportions in the urine of older people. Formation of lipofuscin was thought to result from the activity of free radicals.

Lipofuscin, structurally and chemically, was very similar to another substance called neuromelanin, which was responsible for the black hue of cells in a healthy "substantia nigra". Some doctors postulated that the accumulation of neuromelanin promoted cellular dysfunction.

Examination of post-mortem brains of Parkinson's disease sufferers show that in the "substantia nigra" of these brains there was a shortage of the chemical scavengers that attacked free radical molecules. The Parkinson's Study Group decided to use Deprenyl as a therapy to examine the effects of oxidative processes on the death of cells in the "substantia nigra". Deprenyl demonstrated to have an specific antioxidative effect. As an monoamine oxidase inhibitor, it seemed to discourage the degradation of dopamine, the neurotransmitter whose absence was associated with the presence of Parkinson's disease ^32,33.

Deprenyl had been proven to be a safe drug, showing that slows the progressive degeneration of "substantia nigra" neurons and resulting clinical decline of Parkinson's disease.

There are three theories to explain the possible mechanism of action of Deprenyl in protecting neurons in Parkinson's patients:

1. Since small quantities of amphetamine and L-metamphetamine are derived from the metabolism of Deprenyl, there is the possibility that chronic exposures to these metabolites might produce changes in dopamine turnover or dopamine receptor function.

2. Another possibility is through the action of 2-phenylethylamine which is increased substantially when monoamine oxidase B is inhibited by Deprenyl, 2-phenylethylamine is a neuromodulator which acts directly upon dopamine receptors and can produce behavioral effects similar to dopamine.

3. And finally is the stimulation of brain activity of superoxide dismutase which counteracts the damaging effects of the superoxide radical produced during the degradation of dopamine by monoamine oxidase-B, also the evidence that Deprenyl is able to inhibit hydrogen peroxide radicals, which are produced as a result of dopamine metabolism.

In an open, uncontrolled study the long-term (9 year's) effect of treatment with Madopar or in combination with Deprenyl have been compared in Parkinsonian patients. In patients who lost their response to conventional Madopar therapy the addition of Deprenyl resulted in a significant recouping of the levodopa effect. The survival analysis reveal a significant increase in life expectancy. Although the mechanism underlying this action of Deprenyl is unknown, the results are interpreted as indicating Deprenyl's ability to prevent or retard the degeneration of striatal dopaminergic neurons, Deprenyl is the first anti-Parkinson drug having such a property. This hypothesis is not farfetched since Deprenyl prevents the degeneration of striatal dopaminergic neurons induced in animals.

Deprenyl facilitates dopaminergic tone in the brain in a peculiar manner and gives satisfactory explanation for the observation that long term Deprenyl treatment prolongs the life span of parkinsonian patients significantly⁶.

. Deprenyl is readily absorbed from the gastrointestinal tract, it is distributed rapidly into the tissues, including the brain. It is the L-form of Deprenyl that is an active monoamine oxidase-B inhibitor, the D-(+)- form being 25 times less active. Deprenyl is metabolized into L-(-)-desmethyl Deprenyl (DES), L-(-)-amphetamine (A) and L-(-)-metamphetamine (MA), mainly in the liver. We measured the steady state concentrations of the metabolites in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's or Alzheimer's diseases who were on continuous Deprenyl therapy. The mean concentrations in serum and CSF were similar, and were not affected by the addition of levodopa¹³.

The mean concentrations of patients with Parkinson's or Alzheimer's diseases were 6.5 ± 2.5 ng/ml for A, 14.7 ± 6.5 ng/ml from MA and 0.9± 0.7 ng/ml for DES. The metabolites of Deprenyl were excreted in urine, and the recovery as metabolites was 87%. Due to the stereospecificity and the low CSF concentrations of the (-)-amphetamine metabolites during the therapy with 10 mg Deprenyl, these metabolites do not seem to contribute significantly to the clinical efficacy of Deprenyl¹³.

cyprenil@cytopharma.com