We previously reported that pretreatment with 9-cis retinoic acid (9cRA) reduced brain infarction in stroke brain (Shen et al., J. Neurosci. Res., 2009). The purpose of this study was to examine the neuroregenerative effect of 9cRA in an animal model of stroke. Adult male rats received a 60-min right middle cerebral artery occlusion (MCAo). Animals were separated into two groups with similar infarction sizes, based on magnetic resonance imaging on day 2 after MCAo. 9cRA or vehicle was given noninvasively via an intranasal route starting from day 3 to day 15 after MCAo. We found that intranasal administration of 9cRA increased brain 9cRA level at 1 h after delivery. Behavioral measurements were carried out in automated activity chambers for 24 h at 2 (before administration of 9cRA or vehicle), 7, and 14 days after MCAo. No difference was found before 9cRA or vehicle injection on day 2. Rats receiving poststroke 9cRA treatment show enhanced recovery in motor function demonstrated by significant increases in horizontal activity, total distance traveled, number of movements, and vertical activity, compared to the control group. To further characterize the mechanisms of this functional recovery, animals were treated with bromodeoxyuridine (BrdU) or vehicle. We found that posttreatment with 9cRA significantly enhanced BrdU immunoreactivity in the subventricular zone and lesioned cortex in stroke rats. 9cRA significantly increased the density of BrdU + cells coexpressing nestin and neuronal nuclei (NeuN) in the lesioned cortex. Taken together, our data support that 9cRA has a neuroregenerative effect in stroke animals. The functional recovery may relate to the de novo genesis of neurocircuits in the ischemic brain.
