From The Editors Perspective: Unlocking the Secrets to Cell Survival and Longevity

K.      Maiese

Abstract

Although our present knowledge of the cellular pathways that modulate injury in the nervous system continues to unfold at an exponential rate, reversal or even prevention of cellular injury in the brain can be less than desired under many circumstances. As a result, elucidating novel therapeutic targets for the treatment of neuronal and vascular injury could be highly beneficial to eliminate disability incurred during acute or chronic degenerative disorders of the nervous system. In this issue of Current Neurovascular Research, we present exciting new work and reviews of the literature of unique neuronal and vascular cellular systems that can have a substantial role during disease entities such as cerebral ischemia, hypertension, Alzheimer's disease, and multiple sclerosis. Further understanding of these cellular pathways should foster the safe and efficacious translation of this knowledge into robust therapeutic regimens that allow clinical research to become "practice" rather than only "promise".

In an original article by Chong et al., we learn that nicotinamide, a precursor for the coenzyme ß-nicotinamide adenine dinucleotide (NAD+), has a double life in regards to its effects on cell biology. Nicotinamide is utilized by the body for cellular metabolism through the generation of adenosine triphosphate in the mitochondrial electron transport chain. Yet, this interesting nutrient also is linked to cellular lifespan. Increased longevity, at least in yeast and adult metazoans, is dependent upon sirtuin 2 (Sir2) protein expression and an enzyme that deaminates nicotinamide to convert it into nicotinic acid, namely pyrazinamidase/nicotinamidase 1 (PNC1). When nicotinamide cell concentrations are absent or minimal, Sir2 is activated and PNC1 expression is increased to lead to yeast lifespan extension during calorie restriction. On the flip side, when nicotinamide is present in the cell at higher concentrations, this essential nutrient can function as an inhibitor of sirtuins and offer protection against cerebral ischemia, spinal cord injury, brain trauma, excitotoxicity, and oxidative stress. Chong et al. provide us with further insight into the cellular mechanisms responsible for the ability of nicotinamide to offer cellular protection. In an anoxic cellular model, they show that a cascade of pathways controlled by nicotinamide are intimately connected to involve activation of Akt1, phosphorylation of Bad, prevention of mitochondrial permeability, and the maintenance of poly(ADP-ribose) polymerase integrity to protect against early apoptotic membrane phosphatidylserine residue exposure and subsequent genomic DNA degradation.