tretinoin and Cognitive-Dysfunction

The history of vitamin A goes back over one hundred years, but our realization of its importance for the brain and cognition is much more recent. The brain is more efficient than other target tissues at converting vitamin A to retinoic acid (RA), which activates retinoic acid receptors (RARs). RARs regulate transcription, but their function in the cytoplasm to control nongenomic actions is also crucial. Controlled synthesis of RA is essential for regulating synaptic plasticity in regions of the brain involved in learning and memory, such as the hippocampus. Vitamin A deficiency results in a deterioration of these functions, and failure of RA signaling is perhaps associated with normal cognitive decline with age as well as with Alzheimer's disease. Further, several psychiatric and developmental disorders that disrupt cognition are also linked with vitamin A and point to their possible treatment with vitamin A or RA.

Topics: Animals; Cognition; Cognitive Dysfunction; Humans; Tretinoin; Vitamin A

There is increasing interest in retinoic acid (RA) as a regulator of the complex biological processes underlying the cognitive functions performed by the brain. The importance of RA in brain function is underlined by the brain's high efficiency in converting vitamin A into RA. One crucial action of RA in the brain is dependent on RA receptor α (RARα) transport out of the nucleus, where it no longer regulates transcription but carries out non-genomic functions. RARα, when localised in the cytoplasm, particularly in neuronal dendrites, acts as a translational suppressor. It regulates protein translation as a crucial part of the mechanism maintaining homoeostatic synaptic plasticity, which is characterised by neuronal changes necessary to restore and balance the excitability of neuronal networks after perturbation events. Under normal conditions of neurotransmission, RARα without ligand suppresses the translation of proteins. When neural activity is reduced, RA synthesis is stimulated, and RA signalling via RARα derepresses the translation of proteins and synergistically with the fragile X mental retardation protein allows the synthesis of Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors that re-establish normal levels of synaptic activity. Homoeostatic synaptic plasticity underlies many cognitive processes, so its impairment due to dysregulation of RA signalling may be involved in neurodevelopmental disorders such as autism, which is also associated with FMRP. A full understanding of RA signalling control of homoeostatic synaptic plasticity may point to treatments.

Topics: Cognitive Dysfunction; Homeostasis; Humans; Neuronal Plasticity; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Tretinoin

Retinoic acid (RA), an active metabolite of vitamin A, possesses enormous protective effects on vascular systems. It may also be positively related to good functional outcome after ischemic stroke. However, whether circulating RA concentration is associated with poststroke cognitive impairment (PSCI) remains unclear. This study aimed to detect the association between RA level and PSCI among patients with first-ever acute ischemic stroke.. Two hundred and 61 consecutive patients were prospectively recruited during March 2018 and March 2019. Serum RA concentration was measured at admission for all patients. We also performed cognitive function examination using the Montreal Cognitive Assessment (MoCA) at admission and at every follow-up visit. Patients with MoCA score less than 26 were identified as developing PSCI.. The median serum RA level was 2.0 ng/mL (interquartile range, 1.1-3.2 ng/mL) after admission. Patients diagnosed as PSCI at admission, 1-month and 3-month were 53 (20.3%), 91 (34.6%), and 141 (54.0%), respectively. Univariate analysis showed that reduced RA level was correlated with PSCI at 3-month (P = .003), but not at admission (P = .416) and 1-month poststroke (P = .117). After adjusting for all potential confounders, the odds ratio for the lowest tertile of RA, compared with the highest tertile, was 1.97 (95% confidence interval, 1.01-3.83, P = .046) for PSCI at 3 months. Furthermore, multiple-adjusted spline regression model further confirmed the dose-response relationships between RA level and 3-month PSCI (P < .001).. Decreasing serum RA level might be associated with 3-month PSCI in ischemic stroke patients.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Brain Ischemia; Cognition; Cognitive Dysfunction; Female; Humans; Male; Middle Aged; Prognosis; Prospective Studies; Risk Assessment; Risk Factors; Stroke; Time Factors; Tretinoin

Preterm infants exposed to supra-physiological levels of oxygen often have poor executive and memory function associated with reductions in hippocampal volume later in life. We recently showed that adult mice exposed to neonatal hyperoxia have deficits in spatial navigation and increased exploratory behavior associated with hippocampal shrinkage. Retinoids attenuate hyperoxia-induced lung injury in animal models and reduce neonatal chronic lung disease in preterm infants. We hypothesized that retinoid (combination of Vitamin A+Retinoic Acid [VARA]) administration in mice during neonatal hyperoxia would attenuate oxygen-induced cognitive impairment when assessed in adult life. C57BL/6 mouse pups were exposed to hyperoxia (85% oxygen) or air (21% oxygen), in combination with VARA or canola oil (Vehicle) from postnatal day 2 to 14 and then returned to air. Neurobehavioral (Morris water maze, open field and zero maze tests), structural assessments (MRI and histology), and hippocampal protein measurements were performed. Neonatal hyperoxia resulted in spatial navigation deficits and increased exploratory behavior and accompanied by hippocampal shrinkage in adults, all of which were attenuated by VARA administration. During hyperoxia, VARA increased hippocampal phosphorylated and total mammalian target of rapamycin, and synaptophysin levels to a greater extent in hyperoxia compared to normoxia. In conclusion, VARA attenuated neonatal hyperoxia-induced neurobehavioral impairment and associated reductions in hippocampal volume in adult mice, possibly by increasing mTOR signaling and synaptic density. These novel data suggest that retinoids may be neuroprotective in extremely preterm infants at high risk of impairment, and may potentially be effective in other models of oxidant stress as well.

Topics: Animals; Animals, Newborn; Behavior, Animal; Cognition; Cognitive Dysfunction; Hippocampus; Hyperoxia; Maze Learning; Mice; Phosphorylation; Signal Transduction; Spatial Navigation; Synaptophysin; TOR Serine-Threonine Kinases; Tretinoin; Vitamin A