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Hypertension prevents a sensory stimulation-based collateral therapeutic from protecting the cortex from impending ischemic stroke damage in a spontaneously hypersensitive rat model.

ABSTRACT: Assessing potential stroke treatments in the presence of risk factors can improve screening of treatments prior to clinical trials and is important in testing the efficacy of treatments in different patient populations. Here, we test our noninvasive, nonpharmacological sensory stimulation treatment in the presence of the main risk factor for ischemic stroke, hypertension. Utilizing functional imaging, blood flow imaging, and histology, we assessed spontaneously hypertensive rats (SHRs) pre- and post-permanent middle cerebral artery occlusion (pMCAO). Experimental groups included a treatment SHR group (sensory-stimulated group), control untreated SHR group (no sensory stimulation), and a treated (sensory-stimulated) Wistar-Kyoto normotensive group. Unlike our previous studies, which showed sensory-based complete protection from impending ischemic cortical stroke damage in rats as seen in the treated Wistar-Kyoto group, we found that SHRs at 24hr post-pMCAO lacked evoked cortical activation, had a significant reduction in blood flow within the MCA, and sustained very large infarcts regardless of whether they received stimulation treatment. If translatable, this work highlights a potential need for a combined treatment plan when delivering sensory stimulation treatment in this patient population.

SUBMITTER: Hancock AM

PROVIDER: S-EPMC6198990 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Hypertension prevents a sensory stimulation-based collateral therapeutic from protecting the cortex from impending ischemic stroke damage in a spontaneously hypersensitive rat model.

Hancock Aneeka M AM Frostig Ron D RD

PloS one 20181023 10

Assessing potential stroke treatments in the presence of risk factors can improve screening of treatments prior to clinical trials and is important in testing the efficacy of treatments in different patient populations. Here, we test our noninvasive, nonpharmacological sensory stimulation treatment in the presence of the main risk factor for ischemic stroke, hypertension. Utilizing functional imaging, blood flow imaging, and histology, we assessed spontaneously hypertensive rats (SHRs) pre- and ...[more]

PMID: 30352082

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Project description:IntroductionSensorimotor integration is critical for generating skilled, volitional movements. While stroke tends to impact motor function, there are also often associated sensory deficits that contribute to overall behavioral deficits. Because many of the cortico-cortical projections participating in the generation of volitional movement either target or pass-through primary motor cortex (in rats, caudal forelimb area; CFA), any damage to CFA can lead to a subsequent disruption in information flow. As a result, the loss of sensory feedback is thought to contribute to motor dysfunction even when sensory areas are spared from injury. Previous research has suggested that the restoration of sensorimotor integration through reorganization or de novo neuronal connections is important for restoring function. Our goal was to determine if there was crosstalk between sensorimotor cortical areas with recovery from a primary motor cortex injury. First, we investigated if peripheral sensory stimulation would evoke responses in the rostral forelimb area (RFA), a rodent homologue to premotor cortex. We then sought to identify whether intracortical microstimulation-evoked activity in RFA would reciprocally modify the sensory response.MethodsWe used seven rats with an ischemic lesion of CFA. Four weeks after injury, the rats' forepaw was mechanically stimulated under anesthesia and neural activity was recorded in the cortex. In a subset of trials, a small intracortical stimulation pulse was delivered in RFA either individually or paired with peripheral sensory stimulation.ResultsOur results point to post-ischemic connectivity between premotor and sensory cortex that may be related to functional recovery. Premotor recruitment during the sensory response was seen with a peak in spiking within RFA after the peripheral solenoid stimulation despite the damage to CFA. Furthermore, stimulation in RFA modulated and disrupted the sensory response in sensory cortex.DiscussionThe presence of a sensory response in RFA and the sensitivity of S1 to modulation by intracortical stimulation provides additional evidence for functional connectivity between premotor and somatosensory cortex. The strength of the modulatory effect may be related to the extent of the injury and the subsequent reshaping of cortical connections in response to network disruption.

Project description:IntroductionPeripheral arterial disease (PAD) is a major risk factor for lower-extremity amputation in diabetic patients. Unfortunately, previous clinical studies investigating therapeutic angiogenesis using the vascular endothelial growth factor (VEGF) have shown disappointing results in diabetic patients, which evokes the necessity for novel therapeutic agents. The apelinergic system (APJ receptor/apelin) is highly upregulated under hypoxic condition and acts as an activator of angiogenesis. Apelin treatment improves revascularization in nondiabetic models of ischemia, however, its role on angiogenesis in diabetic conditions remains poorly investigated. This study explored the impact of Pyr-apelin-13 in endothelial cell function and diabetic mouse model of hindlimb ischemia.MethodsNondiabetic and diabetic mice underwent femoral artery ligation to induce limb ischemia. Diabetic mice were implanted subcutaneously with osmotic pumps delivering Pyr-apelin-13 for 28 days. Blood flow reperfusion was measured for 4 weeks post-surgery and exercise willingness was assessed with voluntary wheels. In vitro, bovine aortic endothelial cells (BAECs) were exposed to normal (NG) or high glucose (HG) levels and hypoxia. Cell migration, proliferation and tube formation assays were performed following either VEGF or Pyr-apelin-13 stimulation.Results and discussionFollowing limb ischemia, blood flow reperfusion, functional recovery of the limb and vascular density were improved in diabetic mice receiving Pyr-apelin-13 compared to untreated diabetic mice. In cultured BAECs, exposure to HG concentrations and hypoxia reduced VEGF proangiogenic actions, whereas apelin proangiogenic effects remained unaltered. Pyr-apelin-13 induced its proangiogenic actions through Akt/AMPK/eNOS and RhoA/ROCK signaling pathways under both NG or HG concentrations and hypoxia exposure. Our results identified the apelinergic system as a potential therapeutic target for angiogenic therapy in diabetic patients with PAD.

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Hypertension prevents a sensory stimulation-based collateral therapeutic from protecting the cortex from impending ischemic stroke damage in a spontaneously hypersensitive rat model.

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Hypertension prevents a sensory stimulation-based collateral therapeutic from protecting the cortex from impending ischemic stroke damage in a spontaneously hypersensitive rat model.

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