Neuroprotection by a selective estrogen receptor beta agonist in a mouse model of global ischemia.

The present study employs selective estrogen receptor (ER) agonists to determine whether 17beta-estradiol-induced neuroprotection in global ischemia is receptor mediated and, if so, which subtype of receptor (ERalpha or ERbeta) is predominantly responsible. Halothane-anesthetized female C57Bl/6J mice were ovariectomized, and osmotic minipumps containing ERbeta agonist diarylpropiolnitrile (DPN) (8 mg.kg(-1).day(-1), n = 12) or vehicle (50% DMSO in 0.9% saline) (n = 9) or ERalpha agonist propyl pyrazole triol (PPT) (2 mg.kg(-1).day(-1), n = 13) or vehicle (50% DMSO in 0.9% saline) (n = 10) were implanted subcutaneously. One week later transient global ischemia was induced by bilateral carotid artery occlusion under halothane anesthesia, and the mice were perfusion fixed 72 h later. ERbeta agonist DPN significantly reduced ischemic damage by 70% in the caudate nucleus and 55% in the CA1 region compared with vehicle controls (P < 0.05, Mann-Whitney U-statistic). In contrast, pretreatment with the ERalpha agonist PPT had no effect on the extent of neuronal damage compared with controls. The data indicate a significant estrogen receptor-mediated neuroprotection in a global cerebral ischemia model involving ERbeta.

Mitochondrial DNA deletions in acute brain injury.

We hypothesized that generation of free radicals following acute brain injury leads to increased accumulation of mitochondrial DNA deletions. We determined the prevalence of two deletions (mtDNAdelta4977bp and mtDNAdelta7436hP) in brain from 53 patients with a short survival interval (mean 5 days) following transient global cerebral ischaemia due to cardiorespiratory arrest, 14 patients with long survival (mean 8.75 years) following traumatic brain injury and 43 age-matched controls. A higher prevalence of mtDNA delta4977bp was found in aged controls. There was a strong correlation between the presence of the two mtDNA deletions in individual cases (p < 0.05). The deletion prevalence did not differ significantly between short-term survivors of global ischaemia (57% mtDNAdelta4977bP, 62% mtDNAdelta7436bp) and controls (54% mtDNAdelta4977bp, 56% mtDNAdelta7436bp). Unexpectedly, there was a lower prevalence of deleted mtDNA in long-term survivors of traumatic brain injury (14.3% mtDNAdelta7436bp, p < 0.05) raising the possibility that free radical-induced accumulation of mtDNA damage may selectively influence the survival of mitochondria or their host.