Parkinson's disease is a drastic disease that strikes people in their late fifties. In this disorder the sufferers are left without motor control. The loss of motor control causes tremors and difficulties in movement. About forty years ago scientists discovered that the symptoms in Parkinson’s disease were due to the death of brain cells in the substantia nigra where the neurochemical dopamine is produced. Our research has revealed that diet restriction has the potential to rescue dopamine neurons.

These findings may lead to a novel, viable, acceptable treatment for Parkinson's disease; the reasons why dopamine brain cells die are not fully understood. However infection, inflammation and oxidative stress are currently considered as probable candidates that harm these brain cells. Different kinds of inflammatory components including activated microglia, the immune cell of the brain, are noted in Parkinson’s brains near dying dopamine brain cells. The presence of microglia is of particular interest. Microglia may be considered the Jekyll and Hyde of the brain as they can both protect and harm brain cells.

In the healthy brain these cells remain calm or dormant. Any disturbance to the brain causes microglia to arm and prepare to defend the brain. In response to injury the acrobatic microglia changes its shape and function and becomes activated. In an attempt to assist the injured brain microglia become frustrated and add to the neurodegenerative fury by releasing an arsenal of dangerous substances. This cycle once started continues as defenseless neurons die. Knowledge gained about this cascade highly suggests that the survival of brain cells could be improved by interventions which quench activated microglia.

Figure 1 Photomicrographs of the rat substantia nigra following the injection of lipopolysaccharide (LPS). The animal in A was placed on diet restriction 24 hours after the injection of LPS. The section was processed for immunocytochemistry using antibodies to identify activated microglia. Note that the brain region is virtually devoid of immunoreactivity. The animal in B was placed on diet restriction 5 weeks before receiving LPS and was then maintained on a standard diet. Immunocytochemistry revealed the presence of numerous activated microglia (arrows)

This concept provided the basis for our study. Alternative day feeding in rats injected with a substance suggested to kill dopamine cells via microglial activation provided protection for dopamine brain cells. Interestingly these findings suggest that when activated microglia are subdued by diet restriction dopamine neurons survive. There are reports that drugs which target activated microglia have the ability to interfere with neurodegenerative processes and protect neurons. Even though the merit of drugs cannot be disputed there will be limitations, not to mention possible side effects. A more natural means to interfere with activated microglia would be preferred. Reducing calories not only extends life but also protects the brain from perils such as oxygen free radicals and other neurotoxins associated with disease and aging. Findings in this research provide new evidence that cutting calories can protect dopamine neurons from the threats of activated microglia.

Pubic awareness campaigns have emphasized that overeating is a significant risk factor for numerous disorders including diabetes, cardiovascular diseases and cancers. A reduction in calorie intake and increased exercise for a healthy life are emphasized for all ages. Now the same message is emphasizing that this healthy lifestyle may reduce risks for some neurodegenerative disorders. Several studies suggest that a high fat diet renders individuals more susceptible to Parkinson’s disease and that high calorie intake renders them more susceptible to Alzheimer’s disease. Reducing calories assists the brain in fighting age-related oxidative stress and inflammatory reactions. This could postpone the onset of neurodegeneration as both oxidative stress and inflammation are viewed as playing early roles in the development of Alzheimer and Parkinson’s diseases. This means that if inflammation can be controlled early in the disorder then neurons would have a better survival rate.

Figure 2 Photomicrographs of the rat substantia nigra immunostained with anti- tyrosine hydroxylase antibodies, which reveals dopamine neurons. The animal in A was placed on diet restriction 24 hours after the injection of LPS. The section shows the presence of tyrosine hydroxylase immunoreactivity meaning intact dopamine neurons (arrow heads). B This animal is a control and the immunoreactivity in the rat substantia nigra shows the normal distribution of tyrosine hydroxylase immunoreactivity in dopamine neurons (arrows). The animal in C was placed on diet restriction 5 weeks before receiving LPS and was then maintained on a standard diet. Immunocytochemistry revealed the absence of tyrosine hydroxylase staining in the substantia nigra indicating destruction to dopamine neurons (open arrows show the disappearance of dopamine neurons).

From a basic neuroscience point of view understanding the fundamental cellular and molecular mechanisms through which diet restriction subdue microglial activation could be a significant advancement in designing novel treatments to render neurons resistant to insults such as oxidative stress, inflammation and associated neurotoxins. Knowledge of this nature when extended to the human brain could provide means to intervene during the early stages of the neurodegeneration.

Findings that diet restriction protects neurons have been a subject of number of interesting and exciting papers. Publications have revealed that diet restriction has the ability to stimulate neurogenesis, protect dopamine neurons from neurotoxins, protect hippocampal neurons from excitotoxins and extend the life of span of rodents. Moreover diet restriction stimulates the production of neurotrophic factors and increases cognitive function. In essence the use of diet restriction as a means of neuroprotection is not the novel element of our findings. The novelty of our findings is the ability to show that interfering with activated microglia through diet restriction (see figure 1) protects dopamine neurons. Moreover the findings here indicate that beginning diet restriction after the onset of microglial activation was more beneficial to brain cells than starting the regimen before the insult (see figure 2). This is of interest since most studies have shown that diet restriction is beneficial to brain cells when started before the insult. Additionally unlike other experimental approaches, which used neurotoxins to eliminate dopamine neurons, our approach relied on one, which caused dopamine cell death via microglia activation through an injection of lipopolysaccharide. Thus it appears that if an early marker for ongoing inflammatory reactions were available then diet restriction in Parkinson’s disease could be considered as beneficial for rescuing dopamine brain cells.

Further research is needed to focus on establishing the pathway through which diet restriction interferes with microglial activation. For instance are genes affected and if so which ones? Diet restriction is known to increase trophic factors. It is important to know at what level these increases are involved in the present model. Are microglia being affected by diet restriction and if so at what level? A study at the electron microscope level is likely to reveal information about morphological changes in microglia in rats undergoing diet restriction in this model. Moreover since microglia release an arsenal of neurotoxic substances in response to inflammation does diet restriction modify the release of these substances and if so which ones are more affected?

Further knowledge about how lipopolysaccharide causes specific damage to dopamine neurons via microglia activated could indeed provide essential knowledge about the involvement of inflammation in Parkinson’s disease. A time course of the activation of microglia in relation to the death of dopamine brain cells is currently in progress. In view of the fact that there are other means to interfere with inflammation such as diets rich in antioxidants it will be of interest to use the present model to compare these findings to a diet rich in antioxidants.

The brain like the heart and other body organs needs care. Food and exercise are essential for maintaining a healthy brain. A study in mice suggests that lowering calories at any age can extend life and protect the brain from harmful age-related substances. Findings of this research indicate that diet restriction arrests ongoing inflammatory reactions, which cause dopamine brain cell death. Similar brain cells are affected in the human neurodegenerative disorder Parkinson’s disease. Applying this simple intervention to early stages of Parkinson’s disease is a possible means of weakening an inflammatory attack of dopamine brain cells and to extend their survival. Though diet restriction may not provide full benefit to Parkinson’s patients, coupled with other kinds of treatments, it may be a means to extend the survival of dopamine brain cells and enhance the quality of life for persons afflicted with Parkinson’s disease.

Amanda McRae is Professor of Neurology in the Medical School and Jaya Ramchandani is completing her MPhil degree and was a recipient of a Dean’s Award for the work reported above. The research is presently funded by a grant from the UWI Campus Research and Publication Fund.