Cerebral blood flow alteration in neuroprotection following cerebral ischaemia

Abstract

The best neuroprotectant for acute ischaemic stroke would always be the rapid return of oxygen and glucose to physiological levels. This is currently provided by thrombolysis which restores blood flow to the ischaemic region. The attempt to confer neuroprotection by targeting the brain parenchyma has shown promise in experimental stroke models, but has unequivocally failed to translate to the clinic. Neuroprotective therapy primarily targets the biochemical cascade that produces cell death following cerebral ischaemia. However, these agents may also alter signal transduction that controls cerebral blood flow, for example glutamate, which may affect the outcome after ischaemia. In these cases, neuroprotection may potentially be due to the improved access to oxygen and glucose rather than biochemical prevention of cell death. Improvement in cerebral blood flow is an important but often overlooked effect of neuroprotective therapy, analogous to the protective effects of drug-induced hypothermia. This short review will discuss cerebral blood flow alteration and protection of the brain in the context of ischaemic preconditioning, oxygen sensing and thrombolysis. Future neuroprotection studies in cerebral ischaemia require stringent monitoring of cerebral blood flow, plus other physiological parameters. This will increase the chances that any protection observed may be able to translate to human therapy.

Optical imaging of disrupted functional connectivity following ischemic stroke in mice

“…Spontaneous hemodynamic fluctuations within the infarct exhibited significant attenuation over most of the functional connectivity band while the remaining components displayed delayed correlations with contralateral brain regions. These observations are consistent with several other studies reporting alterations in neurovascular coupling following stroke[36] in animals and humans where focal ischemia produced regional changes in basal perfusion[37–39] and cerebrovascular reactivity[40] within lesional and perilesional tissue. Such physiological effects do not exclude the possibility that viable neuronal tissue may still be present within the ischemic core and surrounding regions.…”

Importance of Preclinical Research in the Development of Neuroprotective Strategies for Ischemic Stroke

“…20,26 Similarly, compounds that indirectly affect and improve cerebral blood flow (again including MK801) can confer protection by reducing the severity of the insult rather than exhibiting their purported pharmacological mechanism of action on the brain parenchyma. 27,28 There are also pharmacokinetic differences that need to be taken into account when translating findings to the clinical setting. This can be highlighted by the very promising neuroprotective free radical scavenger, NXY-059; although developed with a preclinical design that addressed many previous limitations, its ability to cross the blood-brain barrier (BBB) and exert its effects in the brain was never clearly demonstrated in humans.…”

Alteplase Treatment does not Increase Brain Injury After Mechanical Middle Cerebral Artery Occlusion in the Rat

“…13 This demonstrates the importance of CBF to the outcome after cerebral ischemia, and that neuroprotective agents may actually modulate CBF to produce their effect. 31 Our data revealed that other parameters such as percentage body weight loss, neuroscore, and the number of PIDs were also correlated with infarction ( Figures 3 and 4). However, it may be the total duration of tissue depolarization and not its frequency that correlates with ischemic injury.…”