Veterans Affairs

Nicotine metabolite as neurodegenerative disease therapeutic

Continine may play a role in boosting the efficacy of current drugs used for the treatment of Alzheimer’s, Parkinson’s and related neural diseases

Medical & Biotechnology

The U.S. Department of Veterans Affairs has developed and conducted initial experiments of a two-component nicotine metabolite for treating neurodegenerative diseases. The patented formulation is available to businesses who would develop the research into an available treatment.

Tobacco smoke is composed of thousands of compounds, most of which have deleterious actions on cell homeostasis resulting in toxic effects over the cardiovascular, pulmonary and brain systems. Despite all of these negative actions, several studies suggest that smoking is protective against Alzheimer’s and Parkinson’s disease. The benefits of tobacco have been attributed to nicotine, the alkaloid and a potent cholinergic agonist present in tobacco. Nicotine has anti-apoptotic actions by a mechanism dependent on nicotinic acetylcholine receptors (nAChRs) and has neuroprotective activity against amyloid-beta peptides (the substance in the plaques and neurofibrillary tangles of AD) toxicity in vitro.

Nicotine is metabolized to cotinine in the liver, which has a longer half-life than nicotine (10-24 hours versus 2-3 hours, respectively) and similar cytoprotective activity. The molecular mechanisms underlying the protective actions of cotinine are not well understood. Cotinine is a weak agonist at the nicotinic and muscarinic ACh receptors (mAChR), and it does not have significant cholinergic effects in the brain.

Given the above, VA researchers have developed and conducted initial experiments of a two-component therapy for Alzheimer’s and Parkinson’s disease. The approach comprises administering a therapeutically effective amount of cotinine, or a pharmaceutically acceptable salt in conjunction with other drugs for the treatment or prevention of neurodegenerative conditions, including, donepezil (ARICEPT), galantamine (RAZADYNE), rivastigmine (EXELON), memantine (AKATINOL), rasagiline (AZILECT), selegiline (ELDEPRYL), L-dopa (LEVODOPA, SINEMET, PARCOPA, STALEVO, MADOPAR), carbidopa (LODOSYN), and benserazide, or an isomer or analog thereof. Other neurodegenerative conditions which may be treated with this method include dementia with Lewy bodies (DLB), dementia pugilistica, Pick’s disease, cerebral amyloid angiopathy, and posterior cortical atrophy.

It is further contemplated that this approach may have therapeutic benefit for patients with Down’s syndrome and PTSD. Because Down’s syndrome patients have a double copy of the amyloid precursor protein gene (APP), they tend to accumulate amyloid-beta protein and eventually develop the neurofibrillary tangles. For the treatment of PTSD, cotinine may be administered with other drugs used in the treatment of stress disorders including MAO inhibitors, antiepileptic drugs, SSRIs and SNRIs to name a few. Researchers have presented in vivo evidence that cotinine could be a treatment for PTSD.

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