Cerebroprotection for Acute Ischemic Stroke: Looking Ahead

Abstract

We search for ischemic stroke treatment knowing we have failed-intensely and often-to translate mechanistic knowledge into treatments that alleviate our patients' functional impairments. Lessons can be derived from our shared failures that may point to new directions and new strategies. First, the principle criticisms of both preclinical and clinical assessments are summarized. Next, previous efforts to develop single-mechanism treatments are reviewed. Finally, new definitions, novel approaches, and different directions are presented. In previous development efforts, the basic science and preclinical assessment of candidate treatments often lacked rigor and sufficiency; the clinical trials may have lacked power, rigor, or rectitude; or most likely both preclinical and clinical investigations were flawed. Single-target agents directed against specific molecular mechanisms proved unsuccessful. The term neuroprotection should be replaced as it has become ambiguous: protection of the entire neurovascular unit may be called cerebral cytoprotection or cerebroprotection. Success in developing cerebroprotection-either as an adjunct to recanalization or as stand-alone treatment-will require new definitions that recognize the importance of differential vulnerability in the neurovascular unit. Recent focus on pleiotropic multi-target agents that act via multiple mechanisms of action to interrupt ischemia at multiple steps may be more fruitful. Examples of pleiotropic treatments include therapeutic hypothermia and 3K3A-APC (activated protein C). Alternatively, the single-target drug NA-1 triggers multiple downstream signaling events. Renewed commitment to scientific rigor is essential, and funding agencies and journals may enforce quality principles of rigor in preclinical science. Appropriate animal models should be selected that are suited to the purpose of the investigation. Before clinical trials, preclinical assessment could include subjects that are aged, of both sexes, and harbor comorbid conditions such as diabetes or hypertension. With these new definitions, novel approaches, and renewed attention to rigor, the prospect for successful cerebroprotective therapy should improve.

Keywords: clinical trial design; cytoprotection; hypertension; ischemia; review.

Figure 1.. Excitatory and inhibitory influences on post-synaptic neurons.

In the development of neuronoprotective treatment, antagonists of the glutamate receptors succeeded in preclinical models. Antagonists targeting the NMDA, AMPA/kainite, and metabotropic receptors all failed in clinical trials. Agents acting on the voltage gated calcium, or L-type, channel are used in treating post-hemorrhage vasospasm, but did not succeed as cerebroprotectants. Agonists of the GABA-A receptor, though promising in preclinical assessment, failed in large, pivotal clinical trials. Figure from the author. Abbreviations: NMDA N-methyl-d-aspartate; AMPA α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid; GABA γ-aminobutyric acid

Figure 2.. Reperfusion injury in the neurovascular unit.

The NVU includes neurons, astrocytes, endothelial cells, pericytes, among other cell types. During reperfusion injury, several processes occur to impede microvascular reflow as well as open the blood brain barrier. During reperfusion, impaired mitochondria generate oxygen and nitrogen free radicals that mediate cell injury pathways throughout the NVU. Injury to endothelial cells triggers platelet aggregation and microthrombosis that can exacerbate perfusion failure. Figure reprinted with permission of Sage Publications.

Figure 3.. Help-me signaling in the neurovascular unit.

In response to injury, neurons generate paracrine signals that reach adjacent astrocytes and microglia, causing activation. Glial activation is pleiotropic, with some protective and some toxic responses. After activation, astrocytes generate paracrine factors that protect neurons from further injury, and promote regeneration. Figure from the author and Dr. Padmesh Rajput, PhD.