Gurmeen Kaur, MBBS
The past few years have seen radical changes in stroke care, development of mechanical thrombectomy as standard of care and, more recently, extension of the time limit to 24 hours in the setting of the DAWN trial. With these changes, exploration of neuroprotective agents is the need of the hour, with an aim to extend the potential window for thrombolytic therapy.
Neuroprotection trials, unfortunately, have a dismal history. Reasons attributed to that may be wrong timing or monotherapy trials. Additionally, designing these trials has been difficult because of difficulty with designing animal models that exactly replicate the stroke penumbra.
The most critical application of neuroprotection is saving the ischemic penumbra in patients with large vessel occlusions. If the intervention can decrease the ischemic core or increase the time to prevent ASPECTS decay and increase the potential time for intervention. Animal studies do suggest that neuroprotective drugs or high flow oxygen can impede the evolution of penumbra into core.
Approaches should include pharmacological and non-pharmacological methods. Among pharmacological agents, potential targets include inhibition of glutamate mediated signaling, calcium signaling, free radicals, or inflammation. Unfortunately, none of these drugs have been found to reproducibly improve outcome in pivotal phase III efficacy trials.
Non-pharmacological interventions look promising, especially because they could be tried in the pre-hospital or ambulance setting. Freezing the penumbra is a key concept in this regard — either enhance the oxygen delivery to the ischemic brain or decrease the brain’s oxygen demand. Normobaric oxygen is one such method that has been shown to slow the progression of the penumbra in rodent models with some success. Other potential therapies under investigation include transient descending aortic balloon occlusion and prehospital arm ischemia in conjunction with tPA.
With the new thrombectomy guidelines, the 4 main aims of neuroprotection will be: extending the window for thrombolytic therapy, preventing and retarding infarct progression, additive effect of neuroprotection and thrombectomy and selective intra-arterial delivery into hypo-perfused brain.
Another target for ‘neuroprotective interventions’ is decreasing reperfusion injury involving breakdown of the blood brain barrier and reactive hyperperfusion. Targets for decreasing or preventing reperfusion injury include decreasing reactive oxygen species, suppressing microglia (minocycline was tried but did not have a positive outcome), and preventing hyperglycemia (uric acid may have some role in that).
The timing of using these neuroprotective interventions can be pre-hospital, post-hospital pre-imaging, post-hospital post-imaging, or pre-endovascular intervention. Use of IV magnesium was tried in the pre-hospital setting in the Fastmag study with neutral results.
The challenges in designing successful neuroprotective agents are plentiful and range from safety assessments to ensuring easier clinical designs like Bayesian MAMS studies (Multi-Arm Multi-Stage). Theoretically, neuroprotection is going to be the next revolutionary step in stroke therapy, and it would be exciting to see these results in the years to come!