Revisiting the timing hypothesis: biomarkers that define the therapeutic window of estrogen for stroke.

Significantly extended life expectancy coupled with contemporary sedentary lifestyles and poor nutrition has created a global epidemic of cardiovascular disease and stroke. For women, this issue is complicated by the discrepant outcomes of hormone therapy (HT) for stroke incidence and severity as well as the therapeutic complications for stroke associated with advancing age. Here we propose that the impact of estrogen therapy cannot be considered in isolation, but should include age-related changes in endocrine, immune, and nucleic acid mediators that collaborate with estrogen to produce neuroprotective effects commonly seen in younger, healthier demographics. Due to their role as modulators of ischemic cell death, the post-stroke inflammatory response, and neuronal survival and regeneration, this review proposes that Insulin-like Growth Factor (IGF)-1, Vitamin D, and discrete members of the family of non-coding RNA peptides called microRNAs (miRNAs) may be crucial biochemical markers that help determine the neuroprotective "window" of HT. Specifically, IGF-1 confers neuroprotection in concert with, and independently of, estrogen and failure of the insulin/IGF-1 axis is associated with metabolic disturbances that increase the risk for stroke. Vitamin D and miRNAs regulate and complement IGF-1 mediated function and neuroprotective efficacy via modulation of IGF-1 availability and neural stem cell and immune cell proliferation, differentiation and secretions. Together, age-related decline of these factors differentially affects stroke risk, severity, and outcome, and may provide a novel therapeutic adjunct to traditional HT practices.

Vitamin D deficiency exacerbates experimental stroke injury and dysregulates ischemia-induced inflammation in adult rats.

Vitamin D deficiency (VDD) is widespread and considered a risk factor for cardiovascular disease and stroke. Low vitamin D levels are predictive for stroke and more fatal strokes in humans, whereas vitamin D supplements are associated with decreased risk of all-cause mortality. Because VDD occurs with other comorbid conditions that are also independent risk factors for stroke, this study examined the specific effect of VDD on stroke severity in rats. Adult female rats were fed control or VDD diet for 8 wk and were subject to middle cerebral artery occlusion thereafter. The VDD diet reduced circulating vitamin D levels to one fifth (22%) of that observed in rats fed control chow. Cortical and striatal infarct volumes in animals fed VDD diet were significantly larger, and sensorimotor behavioral testing indicated that VDD animals had more severe poststroke behavioral impairment than controls. VDD animals were also found to have significantly lower levels of the neuroprotective hormone IGF-I in plasma and the ischemic hemisphere. Cytokine analysis indicated that VDD significantly reduced IL-1α, IL-1ß, IL-2, IL-4, IFN-γ, and IL-10 expression in ischemic brain tissue. However, ischemia-induced IL-6 up-regulation was significantly higher in VDD animals. In a separate experiment, the therapeutic potential of acute vitamin D treatments was evaluated, where animals received vitamin D injections 4 h after stroke and every 24 h thereafter. Acute vitamin D treatment did not improve infarct volume or behavioral performance. Our data indicate that VDD exacerbates stroke severity, involving both a dysregulation of the inflammatory response as well as suppression of known neuroprotectants such as IGF-I.

Intrathecal morphine attenuates recovery of function after a spinal cord injury.

Prior work has shown that a high dose (20 mg/kg) of systemic morphine, required to produce significant analgesia in the acute phase of a contusion injury, undermines the long-term health of treated subjects and increases lesion size. Moreover, a single dose of systemic morphine in the early stage of injury (24 h post-injury) led to symptoms of neuropathic pain 3 weeks later, in the chronic phase. The present study examines the locus of the effects using intrathecal morphine administration. Subjects were treated with one of three doses (0, 30, or 90 microg) of intrathecal morphine 24 h after a moderate contusion injury. The 90-microg dose produced significant analgesia when subjects were exposed to noxious stimuli (thermal and incremented shock) below the level of injury. Yet, despite analgesic efficacy, intrathecal morphine significantly attenuated the recovery of locomotor function and increased lesion size rostral to the injury site. A single dose of 30 or 90 microg of intrathecal morphine also decreased weight gain, and more than doubled the incidence of mortality and autophagia when compared to vehicle-treated controls. Morphine is one of the most effective pharmacological agents for the treatment of neuropathic pain and, therefore, is indispensable for the spinally injured. Treatment can, however, adversely affect the recovery process. A morphine-induced attenuation of recovery may result from increases in immune cell activation and, subsequently, pro-inflammatory cytokine concentrations in the contused spinal cord.