Each year neurological diseases kill approximately 500 million people worldwide. In these diseases, which include Alzheimer’s, Parkinson’s, ALS and stroke, the brain cells responsible for coordinating the activity of the nervous system are irretrievably lost. While it is generally acknowledged that these disorders are separate and distinct clinical entities, increasing evidence has demonstrated they share common etiopathogenic factors.

Neurodegenerative Disease Effects
Although the precise mechanism of cell death in neurodegenerative disease disorders is not known, oxidative stress, mitochondrial dysfunction, glutamate-mediated neurotoxicity and apoptotic processes have all been implicated. The brain is especially vulnerable to oxidative stress due to its rich oxygen supply and high fatty acid content. Glutathione, which is one of the primary antioxidants in the brain, is reduced in Parkinson’s Disease and compensatorily upregulated in Alzheimer’s disease. Markers of lipid peroxidation, protein oxidation and oxidized DNA have been detected in Alzheimer’s and Parkinson’s patients as well.

A second unifying factor in neurodegenerative disease pertains to bioenergetic failure secondary to mitochondrial dysfunction. Neurons consume huge amounts of energy provided by the mitochondria in the form of ATP. Mitochondrial dysfunction, as the result of excessive free radical activity, leads to diminished ATP production. Brain cells become energy starved, normal metabolism is reduced and toxic byproducts are subsequently generated.

A final common pathway in the etiology of neurodegenerative disease involves a process known as glutamate-mediated apoptosis. Apoptosis, also known as programmed cell death, involves the inappropriate activation of specific genes that cleave to DNA and other organelles resulting in gradual cell degradation. Glutamate, an excitatory neurotransmitter, appears to be involved in turning on the apoptotic molecular switch. Glutamate opens specific calcium channels, which subsequently activate protolytic apoptotic gene-related proteins.

Protecting the Brain
The emerging unitary concept of neurodegeneration has profound implications in the development of neuroprotective strategies. Pharmaceutical and/or nutraceutical interventions that target specific pathways in the cascade of cell death may eventually halt the progression of these relentless disorders. Agents that are currently being explored include specific free radical scavengers, mitochondrial substances, antiglutamate compounds and apoptotic inhibitors. It is likely that a cocktail of agents rather than a single factor will be found to be more effective in retarding the pathogenic mechanisms of neurodegenerative disease.

Antioxidants are substances that prevent or repair oxidative damage of cell constituents. Antioxidants are promising agents in the treatment of neurological disease in humans, but many key questions first need to be addressed concerning their clinical use. These questions include whether the antioxidants cross the blood brain barrier or achieve adequate concentrations in specific subcellular locations. The antioxidants that have been most studied to date include vitamin E and specific phytochemicals such as ginkgo biloba.

The best evidence showing the protective effect of antioxidants in Alzheimer’s disease comes from a large scale double-blind, placebo-controlled study of high dose vitamin E (2000 units daily) and Selegiline (10 mg daily) in patients with moderate Alzheimer’s disease. The results of this study indicated that patients taking vitamin E, Selegiline or both reached serious disability end points later than patients on placebo. Many Alzheimer’s disease experts routinely advise high dose vitamin E therapy, usually 800-1000 units twice daily.

Vitamin E therapy has also been studied in Parkinson’s disease. The Deprenyl and Tocopherol antioxidant therapy of Parkinsonism trial was undertaken because data suggested oxidative stress played a role in the pathogenesis of Parkinson’s disease. Unfortunately, vitamin E failed to alter levels of alpha-tocopherol in the spinal fluid of Parkinson’s disease patients. This finding raised questions about the validity of prior negative effects of antioxidant vitamins in the progression of Parkinson’s disease and other neurodegenerative diseases.

Ginkgo biloba is a plant extract that is often said to have beneficial effects on memory. The most studied ginkgo compound is EGB 761, which possesses antioxidant and free radical scavenging activity, reverses age related losses in neurotransmitter receptors, increases choline uptake and downregulates hippocampal glucocorticoid receptors. The specific chemical constituents of EGB 761 are associated with distinct mechanisms of action. Ginkgogolide acts predominantly as an antioxidant and anti-stress compound whereas bilobalide increases mitochondrial ATP production and NMDA (a type of receptor in the brain) receptor antagonism. In a one year double-blind trial, ginkgo was found to exert symptomatic improvement in patients with dementia but many methodological flaws limited the interpretation of these findings. More recently, however, a large multicenter double-blind, placebo controlled trial was undertaken.

Mitochondrial agents include coenzyme Q-10 (CoQ10) and acetyl-carnitine. CoQ10 is a fat soluble quinone, which is responsible for assisting in the mitochondrial electron transport chain. In addition to its role in energy utilization, CoQ10 may also function as a free radical scavenger exerting beneficial effects on cell membrane stability. CoQ10 increases mitochondrial enzyme activity and protects mitochondria from free radical damage. CoQ10 has been found to be protective to dopamine manufacturing neurons and is neuroprotective in animal models of Parkinson’s disease. In an open-label study of CoQ10 in 15 subjects with Parkinson’s disease, all administration led to a substantial increase of plasma CoQ10 levels in treated patients. However, CoQ10 did not improve motor rating scales. Currently a large multicenter study is being conducted to evaluate the use of CoQ10 in Parkinson’s patients.

Acetyl-carnitine is another mitochondrial supporting supplement. It possesses several beneficial neurological properties including the modulation of brain energy metabolism, the production of essential neurotrophic factors and the stimulation of cholinergic synaptic pathways. Acetyl-carnitine also reduces the exitotoxic potential of amyloid peptides implicated in the pathogenesis of Alzheimer’s disease and is reported to have beneficial effects in Alzheimer’s patients.

Huperzine is an alkaloid isolated from Chinese club moss. It possesses two distinct mechanisms of action that make it an ideal candidate for the treatment of patients with Alzheimer’s disease. First, it inhibits an enzyme known as acetylcholinesterase. Acetylcholinesterase is responsible for the degradation of acetylcholine. By inhibiting acetylcholinesterase, huperzine increases brain levels of acetylcholine, the primary neurotransmitter involved in cognition. Second, huperzine inhibits glutamate receptors and prevents excitoxicity. Researchers at Walter Reed Hospital, Washington, D.C., demonstrated that huperzine prevented neuronal damage induced by glutamate exposure and downregulated apoptotic associated genes.

Conclusion
Researchers have discovered many of the mechanisms involved in the pathogenesis of neurodegenerative disease. The recognition that oxidative stress, mitochondrial failure, excitotoxic and apoptotic processes are involved in these disorders has greatly assisted in the identification of novel therapeutic agents. Promising candidate compounds include antioxidants such as vitamin E, phytochemicals including ginkgo biloba, mitochondrial factors such as CoQ10 and acetyl-carnitine and the unique huperzine alkaloid isolated from Chinese club moss. It is also increasingly recognized that a protective brain cocktail may slow disease progression more effectively than a single pharmaceutical or nutraceutical agent.

About the author:
Dr. Jay Lombard is an assistant clinical professor of neurology at New York Presbyterian Hospital and Cornell Medical School and director of the Brain Behavior Center, Rockland County, NY. He can be reached at braincures@yahoo.com.