ALDH2 Activity Recovery by nicotinamide adenine dinucleotide (NAD+) Treatment In Neuroblastoma SH-SY5Y Cells Exposed To Lead And Ethanol

DEZA PONZIO, ROMINA; CEJAS, ROMINA B; ALBRECHT, PAULA A.; FERNANDEZ HUBEID, LUCIA; CANCELA, LILIANA MARINA; IRAZOQUI, FERNANDO J; VIRGOLINI, MIRIAM B

Congreso; 51st Anual Congress. Sociedad Brasilera de Farmacología y Terapéutica; 2019

INTRODUCTION: Several evidences demonstrate that the neurotoxicant lead (Pb) induces neurobehavioral alterations, including an altered response to drugs. We have previously reported that perinatally-Pb-exposed rats showed elevated ethanol (EtOH) intake. It is known that EtOH metabolism determines its motivational properties. In fact, centrally-formed acetaldehyde (ACD) promotes EtOH consumption, while peripheral ACD accumulation induces aversive effects. In both cases, aldehyde dehydrogenase (ALDH) is responsible for ACD oxidation to acetic acid, an step determined by nicotinamide adenine dinucleotide (NAD+) availability. In the Pb-exposed rats, the elevated EtOH intake seems to be mediated by brain ACD accumulation, probably due to a reduced mitochondrial ALDH (ALDH2) activity and expression evidenced in these animals. METHODS: In search of a mechanistic approach, in vitro experiments were performed in SH-SY5Y cells, aimed to evaluate ALDH2 activity in a brain like-environment. Neuroblastoma cells were exposed to Pb (5-200µM), EtOH (100-200 mM) or Pb plus EtOH (10µM/200mM) for 24 h. RESULTS AND CONCLUSION: The results resembled the in vivo data showing that Pb alone (5µM and 10µM) or in combination with EtOH inhibited ALDH2 activity in SH-SY5Y cells. Concomitant supplementation with 1mM NAD+ seems to recover the enzyme activity. Provided the importance of NAD+ in EtOH metabolism, the results suggest either a reduction in NAD+ bioavailability or an altered affinity of the enzyme for its cofactor as a putative combined mechanism of the neurotoxic effects of Pb and EtOH in neuroblastoma-derived cells. Current studies are focalized in the assessment of ALDH2 expression and mitochondrial functionality in this model to explore the mechanisms that modulate ALDH2 function and ACD toxicity in the presence of Pb and EtOH. KEY WORDS: Lead-exposure, Ethanol, ALDH2, NAD+