The Efficacy of an Allosteric Modulator of the Alpha 7 Nicotinic Acetylcholine Receptor in a Murine Model of Stroke

Katherine Hernandez Nathan Jones Sterling B Ortega ^*

• University of North Texas Health Science Center, Fort Worth, United States

Ischemic strokes contribute significantly to cardiovascular-related deaths in the U.S., with current interventions limited to thrombolytic agents. However, these agents present challenges such as a limited therapeutic window, incomplete reperfusion rates, risk of transformation, reperfusioninduced inflammation, and a lack of promoting neuroprotection. We investigated an additional strategy in which prior studies indicated a neuroprotective role. Using a murine transient middle cerebral artery occlusion (tMCAO) model, we evaluated the neurotherapeutic efficacy of a positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor (α7-nAChR), PNU-120596 (PNU), by assessing sensorimotor function, neuropathology, and neuroinflammation. In contrast to previous rat studies that demonstrated improvements in clinical outcomes, a single administration of PNU following stroke induction led to a reduction in acute neuropathology but did not produce a significant improvement in clinical outcomes. Prolonged treatment showed no significant changes in acute neuropathology or sensorimotor function. Additionally, an assessment of neuroinflammation revealed no changes in CD4 T-cell cellularity or phenotype. These findings, alongside prior studies, suggest that the therapeutic efficacy of PNU may be contingent upon the timing of administration, dosage, and pharmacokinetics.