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Thrombin induces ischemic LTP (iLTP): implications for synaptic plasticity in the acute phase of ischemic stroke.

ABSTRACT: Acute brain ischemia modifies synaptic plasticity by inducing ischemic long-term potentiation (iLTP) of synaptic transmission through the activation of N-Methyl-D-aspartate receptors (NMDAR). Thrombin, a blood coagulation factor, affects synaptic plasticity in an NMDAR dependent manner. Since its activity and concentration is increased in brain tissue upon acute stroke, we sought to clarify whether thrombin could mediate iLTP through the activation of its receptor Protease-Activated receptor 1 (PAR1). Extracellular recordings were obtained in CA1 region of hippocampal slices from C57BL/6 mice. In vitro ischemia was induced by acute (3 minutes) oxygen and glucose deprivation (OGD). A specific ex vivo enzymatic assay was employed to assess thrombin activity in hippocampal slices, while OGD-induced changes in prothrombin mRNA levels were assessed by (RT)qPCR. Upon OGD, thrombin activity increased in hippocampal slices. A robust potentiation of excitatory synaptic strength was detected, which occluded the ability to induce further LTP. Inhibition of either thrombin or its receptor PAR1 blocked iLTP and restored the physiological, stimulus induced LTP. Our study provides important insights on the early changes occurring at excitatory synapses after ischemia and indicates the thrombin/PAR1 pathway as a novel target for developing therapeutic strategies to restore synaptic function in the acute phase of ischemic stroke.

SUBMITTER: Stein ES

PROVIDER: S-EPMC4300504 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Project description:BackgroundPrevious experimental studies have found that ischemic post-conditioning exhibits neuroprotective effects by alleviating ischemia-reperfusion injury in an acute ischemic stroke model, and its efficacy is thought to be related to the duration of ischemic post-conditioning. However, ischemic post-conditioning has not been used in patients with acute ischemic stroke. This study aims to determine the safety, tolerability, and maximum tolerable duration of ischemic post-conditioning in patients with acute ischemic stroke receiving mechanical thrombectomy.MethodsPatients with acute ischemic stroke with unilateral middle cerebral artery M1 segment occlusion eligible for mechanical thrombectomy will be enrolled. We adopt a 3 + 3 dose-escalation design with a duration escalation schedule of 0, 1, 2, 3, 4, and 5 min × 4 cycles for the ischemic post-conditioning study. After successful reperfusion following mechanical thrombectomy, the balloon for ischemic post-conditioning will be inflated at the site proximal to the culprit lesion four times for 0-5 min with low-pressure (3-4 atmospheres) inflations, each separated by 0-5 min of reflow. We pre-defined the major responses (vessel perforation or rupture, reocclusion of the culprit vessel after ischemic post-conditioning, vessel dissection, severe vasospasm, ischemic post-conditioning related thrombotic events, and rupture of the balloon used for ischemic post-conditioning) as the stopping rules. Each patient will undergo a rigorous evaluation to determine the safety, tolerability, and maximum tolerable duration of ischemic post-conditioning.DiscussionThis will be the first clinical study to ascertain the safety and tolerability of ischemic post-conditioning in patients with acute ischemic stroke receiving mechanical thrombectomy. The maximum tolerable duration obtained in this study will also serve as a starting point for future studies on the efficacy of ischemic post-conditioning.Clinical trial registration[https://clinicaltrials.gov], identifier [NCT05153655].

Project description:Local cerebral hypoperfusion causes ischemic stroke while driving multiple cell-specific responses including inflammation, glutamate-NMDAR-mediated neurotoxicity, edema formation and angiogenesis. Despite the relevance of these pathophysiological mechanisms for disease progression and outcome, molecular determinants controlling the onset of these processes are only partially understood. In this context, our study intended to investigate the functional role of EphB2 – a receptor tyrosine kinase that is crucial for synapse function and binds to membrane-associated ephrin-B ligands. Cerebral ischemia was induced in EphB2-deficient mice by transient middle cerebral artery occlusion followed by different times (6, 12, 24 and 48 h) of reperfusion. Histological, neurofunctional and transcriptome analyses indicated an increase in EphB2 phosphorylation under these conditions and attenuated progression of stroke in EphB2-deficient mice. Moreover, while infiltration of microglia/macrophages and astrocytes into the peri-infarct region was not altered, expression of the pro-inflammatory mediators MCP-1 or IL-6 was decreased in these mice. In fact, in vitro analyses indicated that binding of EphB2 to astrocytic ephrin-B ligands stimulates NF-κB-mediated cytokine expression via the MAPK pathway. Further magnetic resonance imaging of the EphB2-deficient ischemic brain revealed a lower level of neuronal cytotoxic edema formation within 6 h upon onset of reperfusion. On the mechanistic level, absence of neuronal EphB2 decreased the mitochondrial Ca2+ load upon activation of NMDAR but not AMPAR. Moreover, activation of EphB2 by ephrin-B2 enhanced the NMDA-evoked excitotoxic neuronal cell death in vitro while neuron-specific loss of ephrin-B2 reduced the extent of cerebral tissue damage in the acute phase of ischemic stroke. Collectively, EphB2 may promote the immediate response to an ischemia-reperfusion event in the central nervous system by (i) pro-inflammatory activation of astrocytes via ephrin-B-dependent signalling and (ii) amplification of the NMDA-evoked neuronal excitotoxicity.

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Thrombin induces ischemic LTP (iLTP): implications for synaptic plasticity in the acute phase of ischemic stroke.

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