Dexpramipexole improves bioenergetics and outcome in experimental stroke.
Dexpramipexole, a drug recently tested in patients with amyotrophic lateral sclerosis (ALS,) is able to bind F1Fo ATP synthase and increase mitochondrial ATP production. Here, we have investigated its effects on experimental ischaemic brain injury.



The effects of dexpramipexole on bioenergetics, Ca2+fluxes, electrophysiological functions and death were evaluated in primary neural cultures and hippocampal slices exposed to oxygen-glucose deprivation (OGD). Effects on infarct volumes and neurological functions were also evaluated in mice following proximal or distal middle cerebral artery occlusion (MCAo). Distribution of dexpramipexole within the ischaemic brain was evaluated by means of mass spectrometry imaging.



Dexpramipexole increased mitochondrial ATP production in cultured neurons or glia and reduces energy failure, prevents intracellular Ca2+overload and affords cytoprotection when cultures are exposed to OGD. This compound also counteracted ATP depletion, mitochondrial swelling, anoxic depolarization, loss of synaptic activity and neuronal death in hippocampal slices subjected to OGD. Post-ischaemic treatment with dexpramipexole, at doses consistent with those already used in ALS patients, reduced brain infarct size and ameliorated neuroscore in mice subjected to transient or permanent MCAo. Notably, the concentrations of dexpramipexole reached within the ischaemic penumbra equalled those found neuroprotective in vitro.



Dexpramipexole, a compound able to increase mitochondrial F1Fo ATP-synthase activity reduced ischaemic brain injury. These findings, together with the excellent brain penetration and favourable safety profile in humans, make dexpramipexole a drug with realistic translational potential for the treatment of stroke.



This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
Mirko
M
Muzzi
Department NEUROFARBA, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
Elisabetta
E
Gerace
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
Daniela
D
Buonvicino
Department NEUROFARBA, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
Elisabetta
E
Coppi
Department NEUROFARBA, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
Francesco
F
Resta
Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain.
Laura
L
Formentini
Mass Spectrometry Service Centre (CISM), University of Florence, Florence, Italy.
Riccardo
R
Zecchi
Mass Spectrometry Service Centre (CISM), University of Florence, Florence, Italy.
Laura
L
Tigli
Department of Clinical and Experimental Medicine, Research Unit of Histology & Embryology, University of Florence, Florence, Italy.
Daniele
D
Guasti
Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.
Martina
M
Ferri
Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.
Emidio
E
Camaioni
Department NEUROFARBA, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
Alessio
A
Masi
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
Domenico E
DE
Pellegrini-Giampietro
Department NEUROFARBA, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
Guido
G
Mannaioni
Department of Clinical and Experimental Medicine, Research Unit of Histology & Embryology, University of Florence, Florence, Italy.
Daniele
D
Bani
Department NEUROFARBA, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
Anna M
AM
Pugliese
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
Alberto
A
Chiarugi
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects*; D005071:Evoked Potentials / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000077487:Pramipexole; D061251:Primary Cell Culture; D051381:Rats; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism
D052160:Benzothiazoles; D018696:Neuroprotective Agents; D000077487:Pramipexole; D000255:Adenosine Triphosphate; D002118:Calcium