L‐NAME cotreatment did prevent neither mitochondrial impairment nor behavioral abnormalities in adult Wistar rats treated with vitamin A supplementation

Abstract

Vitamin A has been characterized as a potential neurotoxin, because ingestion of such vitamin - or its derivatives, the retinoids - at moderate to high doses elicits a myriad of deleterious effects, from acute intoxication involving head-ache, confusion, and 'pseudo tumor cerebri' to chronic, and perhaps irreversible, abnormalities, including irritability, anxiety, depression, and suicide ideation. Nevertheless, it still remains to be found the mechanism by which vitamin A induces cognitive decline. Based on the fact that vitamin A at clinical doses is a potent pro-oxidant agent to the central nervous system, we performed the present work to analyze whether a cotreatment with L-NAME at 30 mg/kg (four times a week) was able to prevent (or minimize) the biochemical and/or behavioral disturbances resulting from a 28-day daily supplementation with retinol palmitate at doses from 1000 to 9000 IU/kg/day. Then, we investigated mitochondrial function, redox parameters, and the levels of proteins potentially involved in neurodegenerative events, as for instance α-synuclein and receptor for advanced glycation endproducts. Besides, monoamine oxidase enzyme activity was quantified in this work. We observed that L-NAME cotreatment was not completely effective in preventing the redox disturbances induced by vitamin A supplementation. Moreover, L-NAME cotreatment did not affect the behavioral deficits elicited by vitamin A supplementation. We conclude that other parameters rather than NO levels or its derivatives, as for example ONOO(-), take a more important role in mediating the negative effects triggered by vitamin A supplementation.

Vitamin A and Retinoids as Mitochondrial Toxicants

“…In order to investigate whether NO • production (as indirectly assessed through 3-nitrotyrosine formation) participates in mitochondrial dysfunction and behavioral disturbances observed in the experimental model of vitamin A supplementation, the role of a cotreatment with L-NG-nitroarginine methyl ester was tested (L-NAME; 30 mg/kg four times a week), a nonspecific nitric oxide synthase (NOS) inhibitor, on such parameters. Interestingly, L-NAME cotreatment did not exert any effect on the redox unbalance elicited by vitamin A on rat frontal cortex, hippocampus, substantia nigra, and striatum [ 77 ].…”

“…In fact, α -synuclein may bind to the inner mitochondrial membrane in α -helical conformation [ 89 ]. Interestingly, increased levels of α -synuclein, but unaltered levels of β -synuclein, in brain regions of vitamin A-treated rats were demonstrated [ 67 , 71 , 77 ]. However, neither alterations in α -synuclein structure nor interactions of such protein with mitochondria in the experimental model of vitamin A supplementation were investigated.…”

“…On the other hand, it was shown that vitamin A supplementation for 28 days increased monoamine oxidase (MAO) enzyme activity in both areas of the nigrostriatal axis and hippocampus [ 71 , 77 , 90 ] ( Table 3 ). MAO is responsible for the chemical inactivation of dopamine and serotonin and produces H 2 O 2 in such reaction [ 87 , 91 ].…”