Saturday, 24th August 2019

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PIE Council

General Council Members IX

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Hugo R. Arias PhD
Professor of Pharmacology and Biochemistry
Department of Medical Education (Full-time)

Education
Chemist; Lic. in Biochemistry; and Ph.D. in Biochemistry
National Southern University, Argentina

Postdoctoral Experience
1991-1994 University of California at Riverside, CA.
1999-2002 Texas Teach University Health Sciences Center, Lubbock, TX.
2002 (7 months) University of Florida, Gainesville, FL.

Biography

Dr. Arias was appointed Professor of Pharmacology and Biochemistry at the California Northstate University College of Medicine in July, 2012. Dr. Arias was previously Associate Professor at Midwestern University, Glendale, AZ (2007-2012), and Assistant Professor at Western University of Health Sciences, Pomona, CA (2002-2007). He has more than 10 years of experience teaching Pharmacology and Medicinal Chemistry in the USA, and several years of teaching in Argentina.

During 1984-2006, Dr. Arias was appointed Professional Assistant, Professional Associate, Assistant Investigator, and Adjunct Investigator from National Research Council (CONICET; Argentina).

Research
Since 1984 Dr. Arias has worked in the field of ligand-gated ion channels, more particularly on nicotinic acetylcholine receptors (AChRs). In the last 10 years, Dr. Arias has focused his attention on the role of AChRs in drug addiction, depression, and Alzheimer’s disease. He is currently developing novel ligands for the treatment of these diseases. He has obtained several intramural and extramural grants. He has amassed a large number of publications in peer-review journals (74), as well as abstracts and oral presentations (179), editorials (2), and book chapters (15).

Regarding the role of AChRs in nicotine (and drug) addiction, our laboratory is using a variety of approaches at the molecular, neuronal, and whole animal levels. For example, we are studying the pharmacological (i.e., binding affinity, potency, efficacy, receptor selectivity, inhibitory mechanisms) and structural (i.e., characterization of binding site components) properties of drugs that are in the market for smoking cessation therapy (i.e., bupropion and varenicline), as well as drugs that are in clinical stage with demonstrated anti-addictive properties [e.g., 18-methoxycoronaridine (18-MC) and its derivatives] on different human AChR subtypes. For this part of the project, Ca2+ influx, radioligand binding, molecular modeling, docking, and molecular dynamics approaches are used. The role of the b4 subunit in drug (and nicotine) addiction and in the anti-addictive effects mediated by varenicline and 18-MC are being studied by using the behaviour model “cocaine-induced locomotor sensitization” on b4-/- mutant vs wild-type mice (male vs female).

Regarding the role of AChRs in the pharmacological activity of antidepressants, several molecular, structural, and behaviour approaches are being used. For instance, we are studying the pharmacological properties of structurally and functionally different antidepressants that are in the market for depression therapy (i.e., bupropion, SSRIs, NSRIs, and TCAs), drugs that are in the market for smoking cessation therapy (e.g., varenicline), and drugs that are in pre-clinical and clinical stages, on different human AChR subtypes. Electrophysiology experiments have been very helpful to determine that antidepressants inhibit AChRs by different mechanisms. Additional molecular docking and NMR experiments are helping to localize and characterize the antidepressant binding sites (luminal and non-luminal). At the neuronal level, the effects of selective a7 AChR agonists and different antidepressants are being studied by using hippocampal brain slices. At the whole animal level, the antidepressant action of some these compounds is determined by using the behaviour model called “forced swim test”. More specifically, the acute, chronic, and withdrawal activities of these drugs are tested on b4-/- mutant vs wild-type mice (male vs female). Ultimately, these studies will test the hypothesis whether an increased cholinergic activity (or hypersensitivity) over the adrenergic system may result in depression or not.

We are also interested in developing nicotinic ligands that can be used for the treatment of Alzheimer’s disease. There are two opposite hypotheses regarding the involvement of a7 AChRs in the development of Alzheimer’s disease, one that states that the stimulation of a7 AChRs may delay the irreversible development of the Alzheimer’s disease. The development of acetylcholinesterase inhibitors (already in the market), that increase the synaptic concentration of acetylcholine, is based on this hypothesis. The other hypothesis states that the inhibition of a7 AChRs (inhibiting the increased AChR-induced Ca2+ influx elicited by beta amyloid, a peptide expressed in large quantities in Alzheimer’s disease) may delay the Alzheimer’s disease symptoms. To test both hypotheses, we developed two totally different kinds of drugs. For the first hypothesis, we synthesized and pharmacologically characterized a series of novel positive allosteric modulators (PAMs) with high selectivity for a7 AChRs. Since PAMs do not have intrinsic activity but enhance the activity of agonists, we speculate that the activity of these compounds in the brain of Alzheimer’s disease patients can boost the endogenous activity of the neurotransmitter ACh. In fact, animal behavioural studies demonstrated that these PAMs produce pro-cognitive activity per se, probably enhancing the activity of ACh. At the neuronal level, the effects of selective a7 AChR agonists and PAMs, are being studied by using hippocampal brain slices. For the second hypothesis, a series of novel a7 AChR competitive antagonists have been synthesized and characterized. Additional animals behaviour studies (e.g., water maze) will be conducted to determine the behaviour activity of the most promising compounds in terms of increasing memory/cognition, brain faculties that are decreased in Alzheimer’s disease patients.

In conclusion, my laboratory has been actively involved in the characterization of several different nicotinic ligands that can be used as lead compounds for the development of therapies for the treatment of drug addiction, depression, and Alzheimer’s disease.

Editorship
Dr. Arias is currently member of the Editorial Board of several journals, and Associate Editor of the Journal of Pediatric Biochemistry and of the European Journal of Medicinal Plants. He has edited two books and has acted as guest editor on two special issues.

Membership in Professional Societies
Dr. Arias is currently member of The American Society for Cell Biology, Biophysical Society, and the International Society for Neurochemistry.

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