Abstract
The purpose of this study was to examine the neurorestorative effect of delayed 9 cis retinoic acid (9cRA) treatment for stroke. Adult male rats received a 90-min right distal middle cerebral artery occlusion (dMCAo). Animals were separated into two groups with similar infarction sizes, based on magnetic resonance imaging on day 2 after dMCAo. 9cRA or vehicle was given via an intranasal route daily starting from day 3. Stroke rats receiving 9cRA post-treatment showed an increase in brain 9cRA levels and greater recovery in motor function. 9cRA enhanced the proliferation of bromodeoxyuridine (+) cells in the subventricular zone (SVZ) and lesioned cortex in the stroke brain. Using subventricular neurosphere and matrigel cultures, we demonstrated that proliferation and migration of SVZ neuroprogenitor cells were enhanced by 9cRA. Our data support a delayed and non-invasive drug therapy for stroke. Intranasal 9cRA can facilitate the functional recovery and endogenous repair in the ischemic brain.
Highlights
Stroke is the second leading global cause of death in the past decade and a leading cause of adult disability worldwide
We previously reported that pretreatment with 9-cis retinoic acid (9cRA) selectively increased bone morphogenetic protein 7 (BMP7) mRNA expression, reduced brain infarction, and attenuated Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) labeling in stroke brains[16]
Stroke rats were separated into 2 groups with similar lesion sizes, measured by T2 -weighted imaging (T2Wi) on day 2 after distal middle cerebral artery occlusion (dMCAo)
Summary
Stroke is the second leading global cause of death in the past decade (from the WHO, http://www.who.int/mediacentre/factsheets/fs310/en/index.html) and a leading cause of adult disability worldwide. 9cRA is more potent than atRA in promoting neuronal differentiation of human neuroblastoma cells[12] Taken together, these data suggest that 9cRA has neural trophic or reparative properties and may be potentially useful for post-stroke therapy. We previously reported that pretreatment with 9cRA selectively increased BMP7 mRNA expression, reduced brain infarction, and attenuated Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) labeling in stroke brains[16]. These protective effects of 9cRA were antagonized by the BMP antagonist noggin[16]. Since BMP7 has a neuroreparative effect in ischemic brain[19], it is possible that 9cRA can induce neurorepair through BMP7 after stroke
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