High-dose estrogen treatment at reperfusion reduces lesion volume and accelerates recovery of sensorimotor function after experimental ischemic stroke

Abstract

Estrogens have previously been shown to protect the brain against acute ischemic insults, by potentially augmenting cerebrovascular function after ischemic stroke. The current study hypothesized that treatment with sustained release of high-dose 17β-estradiol (E2) at the time of reperfusion from middle cerebral artery occlusion (MCAO) in rats would attenuate reperfusion injury, augment post-stroke angiogenesis and cerebral blood flow, and attenuate lesion volume. Female Wistar rats underwent ovariectomy, followed two weeks later by transient, two-hour right MCAO (tMCAO) and treatment with E2 (n = 13) or placebo (P; n = 12) pellets starting at reperfusion. E2 treatment resulted in significantly smaller total lesion volume, smaller lesions within striatal and cortical brain regions, and less atrophy of the ipsilateral hemisphere after six weeks of recovery. E2-treated animals exhibited accelerated recovery of contralateral forelimb sensorimotor function in the cylinder test. Magnetic resonance imaging (MRI) showed that E2 treatment reduced the formation of lesion cysts, decreased lesion volume, and increased lesional cerebral blood flow (CBF). Ktrans, a measure of vascular permeability, was increased in the lesions. This finding, which represents lesion neovascularization, was not altered by E2 treatment. Ischemic stroke–related angiogenesis and vessel formation was confirmed with immunolabeling of brain tissue and was not altered with E2 treatment. In summary, E2 treatment administered immediately following reperfusion significantly reduced lesion size, cyst formation, and brain atrophy while improving lesional CBF and accelerating recovery of functional deficits in a rat model of ischemic stroke.

Pretreatment with 17β-Estradiol Attenuates Cerebral Ischemia-Induced Blood-Brain Barrier Disruption in Aged Rats: Involvement of Antioxidant Signaling

“…Table S1, www. karger.com/doi/10.1159/000455866), a concentration which was reported to be neuroprotective [31] . To determine whether such exogenous E2 administration could influence aging-related brain injuries during ischemia, these animals were examined 24 h after the induction of MCAO.…”

Sex Differences in Stroke Outcome Are Associated With Constitutive Gut Dysbiosis and Stroke-induced Gut Permeability

“…Bilateral ovariectomy, which decreases circulating levels of estrogens, increases infarct volume in females (Toung et al, 2000a), while estrogen therapy to young females improves stroke outcome (Rusa et al, 1999, Rau et al, 2003, Carpenter et al, 2016, Selvamani and Sohrabji, 2010c. Interestingly, estrogen also reduces infarct volume in males, while the precursor steroid, testosterone, increases infarct volume in this group (Hawk et al, 1998).…”

17β-Estradiol as a Neuroprotective Agent

“…The transient middle cerebral artery occlusion (tMCAO) model followed by reperfusion is one the most frequently used preclinical animal models for testing an agent for its ability to act as a neuroprotectant, that is, to reduce infarct volume and aid in functional recovery [20,24,101,111]. As Figure 7 shows, a dose-dependent reduction of infarct volumes and neurological deficits was observed in DHED-treated animals.…”

“…It is important to emphasize, though, that E2 has a large array of other beneficial effects in the CNS, including regulating body temperature, enhancing cognition and memory and ameliorating neuropsychiatric conditions in both females and males [7,11,[21][22][23]. While the brain is undoubtedly the most frequently studied part of the CNS in the context of neuroprotection [24][25][26], the utility of E2 in protecting the eye (retina and optic nerve) [27][28][29] and spinal cord [30][31][32] have also been explored with promising outcomes.…”