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Acute pathophysiological processes after ischaemic and traumatic brain injury

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Ischaemic stroke and brain trauma are among the leading causes of mortality and long-term disability in the western world. Enormous endeavours have been made to elucidate the complex pathophysiology of ischaemic and traumatic brain injury with the intention of developing new therapeutic strategies for patients suffering from these devastating diseases. This article reviews the current knowledge on cascades that are activated after ischaemic and traumatic brain injury and that lead to progression of tissue damage. Main attention will be on pathophysiological events initiated after ischaemic stroke including excitotoxicity, oxidative/nitrosative stress, peri-infarct depolarizations, apoptosis and inflammation. Additionally, specific pathophysiological aspects after traumatic brain injury will be discussed along with their similarities and differences to ischaemic brain injury. This article provides prerequisites for understanding the therapeutic strategies for stroke and trauma patients which are addressed in other articles of this issue.

Introduction

Stroke is the second most common cause of mortality after cardiovascular disease and one of the leading causes of long-term disability. As such, it poses a massive socio-economic burden worldwide1.

Pathogenetically, stroke encompasses a heterogeneous group of diseases including ischaemic stroke, i.e. stroke due to occlusions of cerebral arteries; hemorrhagic strokes, i.e. primary intracerebral and subarachnoid hemorrhages; and sinus thrombosis. Ischaemic stroke is the result of a transient or permanent reduction of blood flow restricted to the territory of a cerebral artery and is typically caused by an embolic or thrombotic event or cerebral small vessel disease, i.e. in-situ-thrombosis and hyalinosis of small intracerebral arteries and arterioles. Hemodynamic (“watershed”) infarctions as a result of high-grade stenoses of extra- or intracerebral arteries are comparatively rare (less than 5%)2. Ischaemic stroke following such a cerebral vasculo-occlusive event results in dysfunction and death of brain cells.

Established concepts and current understanding of the pathophysiology of ischaemic stroke derive to a substantial degree from animal models, in particular from two fundamentally different rodent models of cerebral ischaemia. One model very closely mimics the clinical situation of an ischaemic stroke by induction of focal cerebral ischaemia. In the other model, global cerebral ischaemia is induced, which simulates the cerebral consequences of cardiac arrest.

The aftermath of a traumatic brain injury (TBI) also places an enormous socio-economic burden worldwide. In the US, for example, TBI is the leading cause of morbidity and mortality after trauma.3

TBI results from an initial acceleration or deceleration of the brain within the bony skull and can be caused, for example, by motor vehicle accidents, fall from a height, assault or, with respect to recent increasing combat-related activities, blast waves from explosions.3, 4 Penetrating TBI is less frequent but refers to a more severe injury and poorer outcome.

In the last few years, several animal models have been designed to mimic the clinical situation of TBI in humans and have provided valuable insight into the pathophysiological mechanisms of TBI. Currently, the most common model is the fluid percussion model, in which injury is induced by a brief fluid pressure pulse applied directly to the intact dural surface. Other models include the rigid indentation, the weight drop, the impact acceleration and the inertial acceleration models (for a review see Ref.5).

The pathophysiological cascades which are activated following ischaemic or traumatic brain injury and which result in the propagation of injury are similar to some extent. We will therefore first discuss the pathophysiological pathways which are activated in the acute phase following cerebral ischaemia. In the second part of this review, we will highlight specific aspects of acute pathophysiological cascades initiated after TBI. Pathophysiological processes which occur in the chronic phase in the post-ischaemic or post-traumatic brain or events which are related to tissue repair and regeneration will not be discussed here since this would go beyond the scope of this review.

Section snippets

The concept of the ischaemic penumbra

The introduction of techniques for measuring regional cerebral blood flow (CBF) provided new insights into the alterations of CBF distribution following cerebral ischaemia. Occlusion of a major cerebral artery produces a severe reduction in CBF in brain areas supplied by that particular artery. However, not all brain cells die immediately following cerebral artery occlusion. Cell death in the affected brain tissue rather evolves in a temporal and spatial continuum. Astrup introduced this

Traumatic brain injury

Human TBI can be caused by an enormous heterogeneity of forces which impact the head. Several experimental models have been established to replicate the different pathogenetic characteristics of TBI. Depending on the nature of forces which act on the head as well as the amount of mechanical energy being transmitted, two major forms of TBI have been classified in humans: closed and penetrating TBI.134 Closed TBI is further sub-classified into static and dynamic loading, depending on the velocity

Concluding remarks

Our pathophysiological understanding of cerebral ischaemia and traumatic brain injury has greatly improved over the last decades due to extensive experimental and clinical research. Complex pathways involving excitotoxicity, oxidative and nitrosative stress, peri-infarct depolarizations, inflammation and apoptosis have been described in models of experimental cerebral ischaemia and TBI. However, so far translation of preclinical results, both in ischaemic stroke and in brain trauma research,

Conflicts of interest

None.

Acknowledgements

This work was supported by the European Union’s Seventh Framework Programme (FP7/2008-2013) under grant agreements no 201024 and no 202213 (European Stroke Network), the Deutsche Forschungsgemeinschaft (NeuroCure Cluster of Excellence, Exc 257) and the Bundesministerium für Bildung und Forschung (Center for Stroke Research Berlin, 01 EO 08 01).

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