Novel Approaches to Neuroprotection Trials in Acute Ischemic Stroke

Cerebral neuroprotection for acute ischemic stroke (AIS) is defined as a therapy aimed at enhancing the brain’s resilience to ischemia to improve the clinical outcome of affected individuals. Although traditionally aimed at the salvage of neurons, this term may be equally applicable to all the cellular constituents of the brain, including cells of cerebral blood vessels, neurons, and glia. Pharmacological neuroprotection (hereafter referred to as neuroprotection) would be achieved by drugs targeting one or more critical components of the ischemic cascade that lead to ischemic damage. The feasibility of neuroprotection has a strong basis in animal experiments, but research for several decades has failed to translate neuroprotective treatments from animals to humans.1–3 The disappointing results of all controlled clinical neuroprotection trials for AIS have cast doubts as to whether neuroprotection in humans is biologically possible and, given the complexities of human stroke syndromes, whether it is a clinically practicable therapy for patients experiencing AIS in the community. The questions of feasibility and practicability cannot be resolved simultaneously. Feasibility is a question of biology: Whether it is possible to achieve tissue sparing after AIS in the high-order brains of humans? The gloomiest hypothesis is that tissue sparing and preservation of neurological function may be possible in low-order species, such as rats, but not in humans. Under this hypothesis, there might be as-yet-unresolved but fundamental anatomic, genetic, or biological differences between low-order species and humans that preclude neuroprotection in the high-order brain. However, recent studies with postsynaptic density-95 (PSD-95) protein inhibitors, a promising class of neuroprotectant that uncouple PSD-95 from neurotoxic signaling pathways in central neurons,4–7 repudiate this concern. They show that neuroprotection is unequivocally possible not only in the rodent brain, but also in the high-order brain of old-world primates8,9 and in …