We examined the effects of age on stroke progression and outcome in order to explore the association between blood-brain barrier (BBB) disruption, neuronal damage, and functional recovery. Using middle cerebral artery occlusion (MCAO), young (3 months) and aged (18 months) rats were assessed for BBB disruption at 20min post-MCAO, and 24h post-MCAO with tissue plasminogen activator induced reperfusion at 120min. Results showed that BBB disruptions in aged rats occurred early and increased nearly two-fold at both the 20min and 24h time points when compared to young animals. Neuronal damage in aged rats was increased two-fold as compared to young rats at 24h, while no neuronal damage was observed at 20min. Young and aged rats exhibited neurological deficits when compared to sham-controls out to 14 days following MCAO and reperfusion; however, aged rats exhibited more severe onset of deficits and prolonged recovery. Results indicate that aged rats suffer larger infarctions, reduced functional recovery and increased BBB disruption preceding observable neuronal injury.

Ischemic stroke is one of the leading causes of morbidity and mortality. Treatment options are limited and only a minority of patients receive acute interventions. Understanding the mechanisms that mediate neuronal injury and death may identify targets for neuroprotective treatments. Here we show that the aberrant activity of the protein kinase Cdk5 is a principal cause of neuronal death in rodents during stroke. Ischemia induced either by embolic middle cerebral artery occlusion (MCAO) in vivo or by oxygen and glucose deprivation in brain slices caused calpain-dependent conversion of the Cdk5-activating cofactor p35 to p25. Inhibition of aberrant Cdk5 during ischemia protected dopamine neurotransmission, maintained field potentials, and blocked excitotoxicity. Furthermore, pharmacological inhibition or conditional knock-out (CKO) of Cdk5 prevented neuronal death in response to ischemia. Moreover, Cdk5 CKO dramatically reduced infarctions following MCAO. Thus, targeting aberrant Cdk5 activity may serve as an effective treatment for stroke.

This study reinforces the importance of using older animals for the researching and treatment of stroke. Elderly animals show differences in response mechanisms, ischemic consequences, and histological changes. These differences may partially explain the current lack of success involved in using young-animal models to predict the clinical efficacy of neuroprotective agents.

No abstract

Neuroinflammation is associated with glial activation following a variety of brain injuries, including stroke. While activation of perilesional astrocytes and microglia following ischemic brain injury is well documented, the influence of age on these cellular responses after stroke is unclear. This study investigated the influence of advanced age on neuronal degeneration, neuroinflammation, and glial activation in female Sprague-Dawley rats after reversible embolic occlusion of the middle cerebral artery (MCAO). Results indicate that in comparison to young adult rats (3 months), aged rats (18 months) showed enhanced neuronal degeneration, altered microglial response, and a markedly increased expression of proinflammatory cytokines/ chemokines following MCAO. In addition, the time-course for activation of STAT3, the signaling mechanism that regulates astrocyte reactivity, was truncated in the aged rats after MCAO. Moreover, the expression of SOCS3, which is associated with termination of astrogliosis, was enhanced as a function of age after MCAO. These findings are suggestive of an enhanced proinflammatory response and a truncated astroglial response as a function of advanced age following MCAO. These data provide further evidence of the prominent role played by age in the molecular and cellular responses to ischemic stroke and suggest that astrocytes may represent targets for future therapies aimed at improving stroke outcome.Keywords neurovascular unit; neuropoietic; IL6; SOCS3; astrocyte; microglia Treatment of acute ischemic stroke injury is hampered by the inability to translate successful animal studies into clinically effective therapies. Despite considerable research interest in specific cardiovascular risk factors for stroke, such as hypertension, hypercholesterolemia, and diabetes, data from the Framingham Heart study demonstrate that age is the single greatest risk factor for stroke (Grossi, 2008). Aging results in enhanced basal expression of proinflammatory cytokines and these same proinflammatory mediators often are associated Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 October 13. with neural injury-related activation of microglia and astroglia. Taken together, the aging, inflammation and glial activation phenotypes serve as the basis for the "inflam-aging" hypothesis (Salvioli et al., 2006;Franceschi et al., 2007;Giunta, 2008). According to this hypothesis, increased inflammation during the aging process results from dysregulation of the immune system and a...