(340b) Investigating the Neuroprotective Effects of 5-Hydroxyadamantane-2-One on Middle-Aged Male Rats in an Ischemic Stroke Model

Introduction: Diamondoids are ultrastable saturated ringed hydrocarbons exhibiting antiapoptotic properties in neurodegenerative disorders including stroke. 5-Hydroxyadamantane-2-one (5-HA-2-one) is one of the derivatives of the simplest diamondoid molecule- adamantane- that is shown to have neuroprotective effects in global transient and local permanent ischemic rat models. However, unfortunately, no studies have evaluated the effectiveness of 5-HA-2-one either in aged animals or at a time point > 30 min following stroke. Therefore, this pilot study examined the neuroprotective effects of 5-HA-2-one on middle-aged male rats 6 hours after MCAo-induced ischemic stroke and compared it to the neuroprotective effects of this drug on mature adult male rats 1 hour and 30 minutes after stroke.

Methods: Mature adult rats (5 months old) and middle-aged (11 months old) Sprague-Dawley male rats were injected with endothelin-1 (ET-1, 600 pmol) stereotaxically toward the middle cerebral artery to induce occlusion (MCAo). 5-HA-2-one (100 mg/kg, i.p.) was administered at 1 hour and 30 minutes post ET-1 and once daily for 4 days to mature adult rats and 6 hour post ET-1 injection and once daily for 4 days to middle-aged rats. Sensory motor behavioral tests were performed pre (-2d) and post (2d and 5d) MCAo. Rats were sacrificed 5 days after MCAo. Brains were sectioned coronally and immersed in 2% 2,3,5-triphenyltetrazolium chloride in DPBS for 30 min at 37°C and processed for imaging. Serum and tissue samples were also collected for biochemical analyses.

Results: This pilot study (n=4) on Mature adult and (n=5) on middle-aged male rats with 5-HA-2-one treatment described above displayed no significant differences in infarct volume (p= 0.813) or on performance of sensory-motor tasks (p=0.866) on middle-aged rats but it showed a significant improvement in sensory-motor behavioral test (p=0.03) on mature adult rats when compared to post-stroke saline treated group. This observation differs from published reports that 5-HA-2-one exhibits neuroprotective effects on mature adult male rats in the early stroke phase 30 min after stroke.

Conclusions: This is the first report of the use of a diamondoid derivative in clinically relevant stroke prone group, the middle aged males, with delayed (> 6 hours) treatment. Our findings suggest that older males may require different strategy (e.g. higher dose and/or earlier treatment) in 5-HA-2-one treatment to exhibit neuroprotective effects. These data underscore the importance of testing potential therapeutic drugs in appropriate preclinical models.

 

Supported by NIH/AG042189 to FS