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Obituary: Toshio Narahashi (1927 – 2013), founding father of neurotoxicology, leader in cellular neuropharmacology

February 02, 2016

Toshio NarahashiToshio Narahashi, widely considered one of the founding fathers of neurotoxicology and a leader in cellular neuropharmacology, died at his Chicago home on April 21, 2013, of complications associated with colon cancer. He was 86. Over a career spanning more than 50 years, Dr. Narahashi was highly decorated from many scientific societies. He was the 2000 Otto Krayer awardee by ASPET, won the K.S. Cole Award from the Biophysics Society, and a Jacob Javits Award. He was especially recognized for his work in neurotoxicology, and he was the first to be awarded the Distinguished Investigator Lifetime Achievement Award in Neurotoxicology in 2001 from the Neurotoxicology Specialty Section of the Society of Toxicology (SOT), the Distinguished Toxicology Scholar Award from the SOT in 2008, and the prestigious Merit Award in 1991.

Dr. Narahashi graduated from the University of Tokyo Faculty of Agriculture with the DVM equivalent in 1948. His scientific career began with studies on the mechanisms of action of insecticides in the Laboratory of Applied Entomology. Already well ahead of his times, Dr. Narahashi used electrical recordings of neuronal and muscle activity to delineate the mechanisms by which chemicals produced their insecticidal action. His findings led to such pivotal observations as the negative temperature-dependence of DDT for its insecticidal action, and the development of knockdown resistance to insecticides ("KDR"). Dr. Narahashi attained international prominence in 1964 when as a visiting researcher at Duke, he made the pivotal discovery that tetrodotoxin, the pufferfish toxin, acted specifically on voltage-gated sodium channels to block nerve conduction. Always maintaining a great sense of humor and perspective, he enlivened his description of the mechanism of action of TTX by recounting the famous confrontation between Agent 007 – James Bond and a Russian agent who poisoned him with TTX from a knife blade in her boot (Ian Fleming, From Russia with Love). Moreover, he would occasionally dine on the delicacy, and desiccated, preserved puffer fish decorated his office at Northwestern University's Feinberg School of Medicine. Dr. Narahashi also described in detail ion channel modulation by other toxins including batrachotoxin, grayanotoxin, and sea anemone toxins, popularizing their use as highly specific chemical tools to study ion channel function. In defining the highly selective mechanism of action of TTX, he elevated the study of toxins and the associated science of toxinology from one of mere biological curiosity to one of such prominence, that biological toxins are now mainstays of experimental studies of excitable cells and signaling processes, and have even become accepted therapeutic agents for treatment of intractable neuropathic pain (omega conotoxin GVIA- Ziconide®) or muscle spasticity (Botulinum toxin A).

Dr. Narahashi also made seminal contributions to our understanding of the role ion channels played in therapeutics. His work with the isolated squid axon at Woods Hole Marine Biological Station demonstrated that local anesthetics act from the inside of the axon after first gaining intraneuronal access in the uncharged form. This information is taught as fact in any introductory pharmacology lectures on mechanisms of local anesthesia. Moreover, his work on squid axon also laid the foundation for the potassium channel blocking action of 4-aminopyridine, a drug FDA approved for treatment in multiple sclerosis and its derivatives, 3,4-diaminopyridine, an orphan drug used in paraneoplastic neuromuscular disorders. His more recent work pointed to ion channel specific actions of general anesthetics and ethanol.

Dr. Narahashi was awarded a Ph.D. in neurotoxicology in 1960 from the University of Tokyo in the old European model of degree conferral based on his 26 full-length publications at the time.

After coming to the U.S., Dr. Narahashi held faculty positions at Duke, rising to vice chairman of the Department of Physiology and Pharmacology before moving to Northwestern University Medical School as chair of pharmacology in 1977. He remained at Northwestern until his death and held the John Evans Professorship in Pharmacology, the highest award at the institution. Not content to rest on his many scientific laurels, Dr. Narahashi oversaw development and rebuilding of a Department of Pharmacology at Northwestern, attracting the best and brightest from around the world. In his last four years as department chair, the Northwestern University Pharmacology Department was ranked #1 in the U.S. out of 100 federally-funded departments for citations/publication, a true statement of his impact as an administrator.

While his work with biological toxins earned him world renown, his research with insecticide neurotoxicity has had an equal or greater societal impact. Dr. Narahashi’s work with insecticides was pivotal to identifying the ion channel basis of insecticidal action of DDT, pyrethroids, dieldren, and others, making him a world leader of insecticide toxicology.

During his scientific career, Dr. Narahashi trained an estimated 140 graduate students and other professionals. These individuals went on to prestigious jobs in academia as well as in the chemical industry at DuPont and BASF, and themselves oversaw dvelopment of newer more biologically safe insecticides. He published 324 papers and 148 chapters and reviews, and edited 11 books. Dr. Narahashi maintained an active teaching profile during his time as department chair, and continued even after the onset of his cancer. In the winter of 2012, he presented the course "Molecular Basis of Drug Action," a treatise on excitable cell physiology biophysics and pharmacology.

He is survived by his wife of 58 years Kyoko; a son, Taro; a daughter, Keiko; two grandchildren; five brothers; and one sister.

 

prepared by Bill Atchison, Ph.D. 

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