Abstract WMP12: Acid-Formulated Malonate Improves Neuroprotection Ischemia-Selective in a Mouse Model of Ischemic Stroke

Background: Malonate, a competitive inhibitor of succinate dehydrogenase, has shown much promise in ameliorating ischemia/reperfusion injury (IRI) in various diseases, including ischemic stroke. Its uptake via the monocarboxylate transporter 1 (MCT1) is enhanced by a decrease in local pH, enabling it to be preferentially taken up by ischemic tissue. We investigated whether an acid-formulated malonate could enhance uptake of malonate and, consequently, protection against stroke IRI. Methods: C57BL/6J mice were treated intravenously with either saline or malonate (640/320 mg/kg) at physiological (7.4) or low pH (6.0). Brain malonate levels were assessed by liquid chromatography-tandem mass spectrometry LC-MS/MS. For the transient middle cerebral artery occlusion (tMCAO) stroke model, mice were subjected to 30 mins ischaemia followed by either 2 hour reperfusion. Brain infarct size was assessed by TTC (2,3,5-triphenyl-2H-tetrazolium chloride) staining. Results: Malonate was acutely protective against stroke IRI with a reduction in brain infarct size from 21.98% to 6.57% after 2 hours of reperfusion. Malonate uptake into the brain in vivo dramatically increased when infused at pH 6 compared to neutral malonate. Furthermore, acid-formulation greatly enhanced the neuroprotective potency of malonate, enabling protection at a much lower dose compared to its non-acidic counterpart. Conclusions: Malonate is neuroprotective against stroke IRI. Its uptake via MCT1 and, ultimately its neuroprotective potency can be enhanced by acid formulation of the drug.