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Tuesday, 28.03.2017

About the author

Joseph Knoll, MD, Professor of Pharmacology Emeritus, Semmelweis Medical University, Budapest, Hungary.  

Knoll’s How Selegiline Slows Brain Aging

Joseph Knoll: How Selegiline Slows Brain Aging. Bentham e Books. (142 pages)

INFORMATION ON CONTENTS: (-)-Deprenyl/Selegiline (D), a phenylethylamine, is a levomethamphetamine derivative with a propargyl group  attached to the nitrogen atom. The substance is registered in 63 countries and marketed world-wide under more than 100 trade-names to treat Parkinson’s disease (PD), Alzheimer’s disease (AD) and major depressive disorder (MDD). D was developed in the early1960s, in the midst of the golden era when within less than 20 years the development of new families of pharmacological agents led to the science of  neuropsychopharmacology which changed the principles of behavioral studies in a revolutionary manner and radically altered human attitudes toward derangements in psychic function. This book looks back to the theoretical foundation of the development of D (Introduction). Chapter 1 briefly summarizes the “First Research Period (1960-1978)” when the drug achieved its place in research and therapy as the first selective inhibitor of B-type monoamine oxidase (MAO). Chapter 2 describes the discovery of the catecholaminergic activity enhancer (CAE) effect of D, and the development of R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane (BPAP), the presently known most potent and selective enhancer substance which exerts this effect in femto-picomolar concentrations. Chapter 3 demonstrates that from weaning until sexual maturity an increased enhancer regulation operates in the catecholaminergic and serotonergic neurons. This mechanism is responsible for the exuberant physical strength and mental vigor in the uphill period of life in mammals. Sex hormones bring back the enhanced enhancer regulation to the pre-weaning level. This mechanism terminates developmental longevity and constitutes the foundation of the transition from adolescence to adulthood. Chapter 4 analyzes the antioxidant and neuroprotective effect of D and their relation to the enhancer effect. Chapter 5 analyzes the aging-related decline of dopaminergic activity and the reason why low dose of D slows brain aging and prolongs life. After analyzing the benefits of D in PD (Chapter 6), AD (Chapter 7) and MDD (Chapter 8), the unique quality of the enhancer substances compatible with lifelong preventive medication to slow brain aging is discussed (Chapter 9). Finally an Appendix summarizes the milestones in D research extracting the most significant papers of the several thousands published on D.

AUTHOR’S STATEMENT: The age-related decay in the supply of the brain with β-phenethylamine (PEA), due to the progressive increase of MAO-B activity in the aging brain, and dopamine, due to the better than average decline of the dopaminergic neuronal activity during the post-developmental phase of life, are biochemical lesions of aging. The speed of deterioration of behavioral performances with the passing of time and longevity depends significantly on the pace of these lesions. D increases the supply of PEA and dopamine in the brain and thereby counteracts the aging process. Our first longevity study has proven that male rats maintained on lifelong D preserved their learning ability longer, lost their ability to ejaculate later, and lived longer than their placebo-treated peers. Due to their CAE effect, D and BPAP, maintain the activity of the catecholaminergic neuronal system on a higher activity level. None of the types of drugs used today to increase catecholaminergic and/or serotonergic neuronal activity in the brain share with D or BPAP the enhancer effect. PEA-derived D and tryptamine-derived BPAP are synthetic analogues of physiological enhancer substances and act accordingly. The enhancer substances do not change the environmental milieu of the enhancer-sensitive neurons when administered in the specific enhancer dose-range. They are just changing the catecholaminergic neuron born with a lower excitability, to a better performing one. In our second longevity study we selected out of a population of 1,600 male rats the 94 sexually lowest performing (LP) males and the 99 highest performing (HP) rats. We treated 44 LP rats with saline and 50 HP rats with D. The saline-treated LP rats lived 134.58 (2.29) weeks, their D-treated peers lived 152.54 (1.36) weeks, as long as the selected saline-treated HP rats (151.24) (1.36 weeks). Thus maintenance on D transformed the low performing rats to high performing ones. Experimental and clinical studies with D strongly support the proposal that preventive administration of a synthetic enhancer substance during post-developmental life could significantly slow the unavoidable decay of behavioral performances with the passing of time, prolong life, and prevent or delay the onset of aging-related neurodegenerative diseases, such as PD and AD. Since D is at present the only worldwide registered CAE substance, in humans, implementation of a properly designed clinical trial on healthy volunteers to measure its anti-aging effect by maintaining subjects on the substance from sexual maturity may be warranted.

Joseph Knoll
September 5, 2013