The neurotoxic effects of vitamin A and retinoids

Abstract

Vitamin A (retinol) and its congeners -the retinoids -participate in a panoply of biological events, as for instance cell differentiation, proliferation, survival, and death, necessary to maintain tissue homeostasis. Furthermore, such molecules may be applied as therapeutic agents in the case of some diseases, including dermatological disturbances, immunodeficiency, and cancer (mainly leukemia). In spite of this, there is a growing body of evidences showing that vitamin A doses exceeding the nutritional requirements may lead to negative consequences, including bioenergetics state dysfunction, redox impairment, altered cellular signaling, and cell death or proliferation, depending on the cell type. Neurotoxicity has long been demonstrated as a possible side effect of inadvertent consumption, or even under medical recommendation of vitamin A and retinoids at moderate to high doses. However, the exact mechanism by which such molecules exert a neurotoxic role is not clear yet. In this review, recent data are discussed regarding the molecular findings associated with the vitamin A-related neurotoxicity.

A role for the liver in parturition and preterm birth

“…In higher concentration, retinoids inhibit cell growth and can be pro-oxidant, cytotoxic, mutagenic, and teratogenic. 15–19 Retinoic acid (RA), the most biologically active metabolite of retinol, is produced from free retinol in a process that involves: 1) hydrolysis of retinyl esters in the liver and the release of retinol into the circulation and its delivery to the target tissues bound to RBP; 2) oxidation of retinol to retinalaldehyde via the action of an alcohol dehydrogenase; and 3) synthesis from retinaldehyde via an aldehyde dehydrogenase reaction, primarily in the cell microsomes. RA exerts its effects by binding to two types of nuclear protein receptors: the retinoic acid receptors (RARs) and retinoid X receptors (rexinoids, RXRs), both of which exist as three distinct gene products (alpha, beta, and gamma).…”

“…At both excessive and therapeutic doses, acute and chronic vitamin A supplementation to laboratory animals leads to increased levels of markers of oxidative stress in liver mitochondria and in the substantia nigra and to alterations in locomotor and exploratory activity. 18,19 …”

Chronic administration of Vitamin C increases cognitive function in chronic stress induced rats

“…In fact, it was demonstrated that vitamin A affects mitochondrial function in vitro and in vivo. [15] However, Kheirvari et al has concluded that high dose of vitamin A may increase BDNF and NGF levels and low dose may decrease BDNF and NGF. [16] The effect would be more pronounced when it is administered along with vitamin E or vitamin C. Studies have reported variable effect of caffeine on LTP and memory whereas the majority studies report LTP and memory enhancement with caffeine [17,18] and few studies report no effect, [19,20] or few even show memory impairment.…”

Vitamin A and the eye: an old tale for modern times

“…Vitamin A topical eye drops may also have utility in the treatment of skin diseases and specific types of cancer including ocular surface neoplasia (52,53) . However, excessive vitamin A intake is known to induce gastric and neural side effects such as abdominal and head pain, nausea, and irritability (54,55) . These symptoms may be aggravated by chronic use of vitamin A eye drops and lead to the development of blurred vision and pseudotumor cerebri (56)(57)(58) .…”