HOW COULD RETINOIDS FIT INTO ALZHEIMER'S THERAPY?

Retinoids are a class of natural and synthetic molecules structurally and/or functionally related to all-trans-retinoic acid (ATRA), a metabolite of Vitamin A (retinol). The retinoid system controls the expression of hundreds of genes, including transcription factors, enzymes, structural proteins, cell surface receptors, neurotransmitters, hormones and growth factors, hence modulating cell proliferation, differentiation, morphogenesis and immunity. The retinoid-associated signaling plays a critical role in neurodevelopment and remains active in the adult central nervous system, thus assuming high relevance in the context of neurodegeneration. The ability of retinoids to exert antioxidant effects, decrease β-amyloid (Aβ) accumulation, improve neurotransmission, suppress neuroinflammation and promote neural regeneration is discussed. Although retinoids with their pleiotropic activity are revealing a promising approach for the management of Alzheimer's disease (AD), timing as well as appropriate dosage and safety still remain a challenge. In particular, assuming that the end-stage lesions (senile plaques and neurofibrillary tangles) are an adaptive response to oxidative stress underlying AD, late administration of retinoids could paradoxically suppress a protective mechanism by inhibiting Aβ deposits

Prenatal exposure to low concentrations of carbon monoxide alters habituation and non-spatial working memory in rat offspring

Inhalation of low concentrations (75 and 150 ppm) of carbon monoxide (CO) by pregnant rats from days 0 to 20 of gestation leads to alterations in habituation and working memory in young adult male offspring subjected to the novel exploration object test. In particular, lack of habituation upon the second presentation of the objects and failure in the ability to discriminate between the novel and the familiar object were found in CO (75 and 150 ppm)-exposed offspring. These alterations were not accompanied by changes in spontaneous motor activity (open field test). The subtle behavioral deficits observed in the present study have been produced by prenatal exposure to CO levels resulting in maternal blood carboxyhaemoglobin (HbCO) concentrations equivalent to those observed in human cigarette smokers

Prenatal exposure model simulating CO inhalation in human cigarette smokers: sphingomyelin alterations in the rat sciatic nerve

Prenatal exposure to low concentrations of carbon monoxide (CO, 150 ppm) causes long-term alterations in sphingomyelin ISM) homeostasis in peripheral nervous system, but not brain of male rat offspring. In particular, unlike sphinganine (intermediate of complex sphingolipid biosynthesis de novo), the concentrations of sphingosine (intermediate of complex sphingolipid turnover) were increased by 2.35-fold in the sciatic nerve of CO-exposed offspring with respect to controls (P < 0.05, overall one-way ANOVA). These subtle alterations were not accompanied by changes in motor activity (F = 0.25, df = 1/10, n.s., overall one-way-ANOVA). The results suggest that the SM homeostasis in the sciatic nerve is particularly susceptible to prenatal CO exposure resulting in maternal carboxyhaemoglobin (HbCO) levels equivalent to those found in human cigarette smokers. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved