tretinoin and Hypoxia-Ischemia--Brain

Our previous studies demonstrated that vitamin A deficiency (VAD) can impair the postnatal cognitive function of rats by damaging the hippocampus. The present study examined the effects of retinoic acid (RA) on apoptosis induced by hypoxic-ischemic damage in vivo and in vitro, and investigated the possible signaling pathway involved in the neuroprotective anti-apoptotic effects of RA. Flow cytometry, immunofluorescence staining and behavioral tests were used to evaluate the neuroprotective and anti-apoptotic effects of RA. The protein and mRNA levels of RARα, PI3K, Akt, Bad, caspase-3, caspase-8, Bcl-2, Bax, and Bid were measured with western blotting and real-time PCR, respectively. We found impairments in learning and spatial memory in VAD group compared with vitamin A normal (VAN) and vitamin A supplemented (VAS) group. Additionally, we showed that hippocampal apoptosis was weaker in the VAN group than that in VAD group. Relative to the VAD group, the VAN group also had increased mRNA and protein levels of RARα and PI3K, and upregulated phosphorylated Akt/Bad levels in vivo. In vitro, excessively low or high RA signaling promoted apoptosis. Furthermore, the effects on apoptosis involved the mitochondrial membrane potential (MMP). These data support the idea that sustained VAD following hypoxic-ischemic brain damage (HIBD) inhibits RARα, which downregulates the PI3K/Akt/Bad and Bcl-2/Bax pathways and upregulates the caspase-8/Bid pathway to influence the MMP, ultimately producing deficits in learning and spatial memory in adolescence. This suggests that clinical interventions for HIBD should include suitable doses of VA.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Caspases; Cells, Cultured; Dietary Supplements; Female; Glucose; Hippocampus; Hypoxia-Ischemia, Brain; Learning; Membrane Potential, Mitochondrial; Mitochondria; Neurons; Oxygen; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Retinoic Acid Receptor alpha; RNA, Messenger; Signal Transduction; Spatial Memory; Tretinoin; Vitamin A; Vitamin A Deficiency

Freeze-lesioned regions of the forebrain cortex provide adequate environment for growth of non-differentiated neural progenitors, but do not support their neuron formation. Reduced oxygen supply, among numerous factors, was suspected to impair neuronal cell fate commitment. In the present study, proliferation and differentiation of neural stem/progenitor cells were investigated at different oxygen levels both in vitro and in vivo. Low (1% atmospheric) oxygen supply did not affect the in vitro viability and proliferation of stem cells or the transcription of "stemness" genes but impaired the viability of committed neuronal progenitors and the expression of proneural and neuronal genes. Consequently, the rate of in vitro neuron formation was markedly reduced under hypoxic conditions. In vivo, neural stem/progenitor cells survived and proliferated in freeze-lesioned adult mouse forebrains, but did not develop into neurons. Hypoperfusion-caused hypoxia in lesioned cortices was partially corrected by hyperbaric oxygen treatment (HBOT). HBOT, while reduced the rate of cell proliferation at the lesion site, resulted in sporadic neuron formation from implanted neural stem cells. The data indicate that in hypoxic brain areas, neural stem cells survive and proliferate, but neural tissue-type differentiation can not proceed. Oxygenation renders the damaged brain areas more permissive for tissue-type differentiation and may help the integration of neural stem/progenitor cells.

Topics: Animals; Antineoplastic Agents; Behavior, Animal; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cell Transplantation; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Green Fluorescent Proteins; Homeodomain Proteins; Hyperbaric Oxygenation; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Ischemia, Brain; Locomotion; Male; Mice; Models, Biological; Nanog Homeobox Protein; Nerve Tissue Proteins; Neural Plate; Neuroepithelial Cells; Oxygen; SOXB1 Transcription Factors; Stem Cells; Time Factors; Transfection; Tretinoin