MAPK and pro-inflammatory mediators in the walls of brain blood vessels following cerebral ischemia
Year: 2012
Type: dissertation
Abstract: INTRODUCTION Stroke is a serious neurological disease which may lead to death and severe disability [1, 2]. There are two major types of stroke: ischemic and hemorrhagic stroke. Both are associated with disruption of blood flow to a part of the brain with rapid depletion of cellular energy and oxygen, resulting in ionic disturbances and eventually neuronal cell death [3]. The pathologic process that develops after stroke is divided into acute (within hours), sub-acute (hours to days), and chronic (days to months) phases [4, 5]. Obviously, the most effective therapy requires the earliest possible intervention e.g. with removal of a thrombus. However, no specific treatment, apart from thrombolysis, that acts effectively to protect the neurons during the acute phase has yet been developed. Experimental and clinical data show an acute and prolonged inflammatory response in the brain after a stroke. Several investigators have reported that inflammation evolves within a few hours after stroke, and plays an important role in the development of the cerebral lesions [6]. This inflammatory reaction involves activation of resident cells (mainly microglia), infiltration and accumulation of various inflammatory cells (including neutrophils, leukocytes, monocytes, macrophages), and production of pro-inflammatory mediators in the injured brain areas [6, 7]. It has been established that the inflammatory reaction triggered by stroke affects not only the neuronal tissue itself but has impact also on the cerebral arteries [7]. Stroke is a vascular disease and despite extensive research in the area, the physiology and pathophysiology of the neurovascular unit, the complex network of endothelial cells, smooth muscle cells, inflammatory cells and mediators are not fully understood, which is necessary in order to develop effective therapies. The aim of the present thesis was to examine the role of pro-inflammatory mediators in cerebrovascular pathophysiology following stroke. The main focus was directed towards the expression and production of cytokines and inducible nitric oxide synthase (iNOS), the activation of matrix metalloproteinases (MMPs) and mitogen activated protein kinase (MAPK) pathway because microarray work [8] and published data [9] primarily pointed at these. These parameters and the relationships between them were studied in the cerebrovascular walls after ischemic and hemorrhagic strokes. This study lends further support to the view that inflammatory mediators are important contributing factors in brain injury after stroke. It provides evidence that blocking the intracellular signaling pathways involved in the transcription of these mediators may have therapeutic potential, as it may prevent or at least attenuate the inflammatory processes elicited by stroke. Ischemic stroke Ischemic stroke is the most common type of stroke (85% of cases). It is caused by a transient or permanent occlusion of a cerebral artery most often by a thrombus or an embolus [10, 11]. When an ischemic stroke occurs, blood flow to an area of the brain is reduced and the brain cells are starved of oxygen and nutrients, which quickly leads to neuronal cell death and the development of an infarct. The infarct region is divided into two parts: 1) A central part or an ischemic core, where the neurons die and have no chance to survive without rapid reperfusion. 2) A peripheral area or an ischemic penumbra, which surrounds the core [12]. Cells in the penumbra are impaired and cannot function due to compromised metabolism, but do not die immediately and have therefore become a prime target for neuroprotective treatments [13-15]. A number of neurochemical and pathophysiological events are triggered within the ischemic penumbra. As a result of energy depletion, there is disruption of ion homoeostasis, excessive release of excitatory neurotransmitters such as glutamate, calcium channel dysfunction, generation of oxidative stress and free radicals, activation of stress signaling, cell membrane disruption, inflammation, ultimately leading to necrotic and apoptotic cell death [1, 4, 15, 16]. The effect of ischemia on brain cells results not only in loss of structural integrity of brain tissue but affects also blood vessels, partly through the activation of inflammatory events and excess production of vasoconstrictor substances and increased receptor expression [17]. The early inflammatory response, which often is associated with the blood vessels, starts immediately or a few hours after the onset of the ischemia and contributes to the irreversible damage [18-21]. Currently, there are two major ways used for treating ischemic stroke: (i) Dissolution of the clot in the occluded artery by a thrombolytic drug, rt-PA (recombinant tissue-plasminogen activator) [22] and, (ii) administration of neuroprotective agents [23]. Treatment with rt-PA is limited by time and should be administered within 4.5 hours after the onset of stroke to reduce the risk of hemorrhagic transformation [24, 25]. Moreover, rt-PA is associated with the risk of disruption to the blood-brain barrier (BBB) which is due to activation of matrix metalloproteinases [26]. Despite intense research, the results obtained with neuroprotective drugs in clinical trials have not revealed positive results [27, 28]. Hemorrhagic stroke Hemorrhagic stroke (15% of all strokes) is often associated with hypertension, and is due to the rupture of an arterial aneurysm or a vascular malformation [1, 29]. Hemorrhagic stroke is divided into two categories: intracerebral and subarachnoid hemorrhage. Intracerebral hemorrhage (ICH) is due to the rupture of a small artery (arterioles) which bleeds within the brain tissue. It is often associated with chronic high blood pressure and the symptoms often begin with severe headache. Subarachnoid hemorrhage (SAH) occurs when an artery or an arterial aneurysm on the surface of the brain ruptures and bleeds into the space between the pia mater and the arachnoid (subarachnoid space) [1]. The most common cause of the SAH is the spontaneous rupture of an arterial aneurysm. This is associated with acute rise of the intracranial pressure (ICP), reduction of cerebral blood flow (CBF), rapid discharge of blood into the basal cisterns, and delayed cerebral ischemia (DCI), each of which may be fatal. The SAH is most common in women and younger people (below 55 years old). Around 50-70% of patients with SAH die or suffer severe disability, and is the cause of up to 10% of all strokes [30-33]. The disease is biphasic, with an early/short-lived phase that occurs immediately after SAH with a reduction in CBF, followed by a chronic or prolonged phase which is characterized by a varying degree of pathological contraction of cerebral arteries, known as vasospasm [34, 35]. The vasospasm (narrowing of arteries) typically occurs within 5-15 days after SAH and is present in approximately one-third of patients and is accompanied by DCI [36, 37]. It can occur not only at the site of the hemorrhage, but also in brain arteries at a distance from the bleeding. The narrowing of the cerebral vessel lumen leads to reduction in local blood flow and in cerebral metabolism, causing severe cerebral ischemia, with increase in mortality of 1.5-3 folds during the first two weeks after SAH [37-39]. Despite intense research, the pathogenesis of DCI after SAH is not well understood and no specific pharmacological treatment is available. Current treatment recommendations involve management in an intensive care unit. The blood pressure is maintained with consideration to the patient’s neurologic status. In addition, calcium channel blockers, endothelin-1 receptor antagonists, hemodynamic management and endovascular treatment are also used, but these treatments are expensive, time-consuming and only partly effective [40]. Many theories have been advanced to explain the mechanisms responsible for vasospasm and DCI that occur after SAH such as, endothelial damage [41-43], enhanced smooth muscle cell (SMC) contractility, morphologic changes in vessel walls [44], enhanced levels of free radicals [45-47], increased production and release of potent vasomotor substances such as endothelin-1 (ET-1) and angiotensin II (Ang II) [48, 49], local inflammation and immunological reactions in the vascular wall [50-52]. Yet, the exact mechanisms underlying the vasospasm and the DCI remain unknown [53]. There is evidence that the amount of blood in the subarachnoid space is related to development of vasospasm [54]. Oxyhemoglobin from extravasated blood may be an important trigger of vasospasm and DCI after SAH [55-57] by inducing inflammation [50, 58]. It may in addition correlate with structural damage to the vessel wall [59], release of spasmogenic substances, and inhibition of endothelium dependent relaxation [60, 61]. It is suggested that the extravasated blood could induce generation of free radicals that subsequently may exert a direct local toxic effect on the cerebral arteries [62, 63]. G-protein coupled receptors following stroke Recently, a novel aspect of the pathophysiology of stroke has been suggested, namely that the upregulation of vasoconstrictor receptors in the cerebral arteries after stroke may be an important mechanism in the development of the final damage [64]. Vasoconstrictor receptors such as those of angiotensin II receptor type 1 (AT1) and endothelin-1 receptor type B (ETB) belong to the seven transmembrane G-protein coupled receptor (GPCR) family [65-67]. They are upregulated in the SMCs of cerebral vessels within and associated with the ischemic region after focal ischemic stroke [68] and after SAH [69]. This results in enhanced contractility of the vessels, which further impairs local blood flow and aggravates tissue damage. Importantly, the receptor ligands (angiotensin II and endothelin-1) are formed in the cerebrovascular endothelium. In addition, contractile responses mediated by AT1 and ETB receptors w
Author: Aida Maddahi
Institution: Lund University
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funder: Lunds Universitet
OpenAlex ID: W2141030356