BACKGROUND AND PURPOSE: To investigate the effects of dexpramipexole, a drug recently tested in ALS patients able to bind F1Fo ATP synthase and increase mitochondrial ATP production, on experimental ischemic brain injury. EXPERIMENTAL APPROACH: 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). The drug's impact on infarct volumes and neurological functions was also evaluated in mice subjected to proximal or distal MCAo. Distribution of dexpramipexole within the ischemic brain was evaluated by means of mass spectrometry imaging. KEY RESULTS: Dexpramipexole boosts 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. The drug also counteracts ATP depletion, mitochondrial swelling, anoxic depolarization, loss of synaptic activity, and neuronal death in hippocampal slices subjected to OGD. Consistently, post-ischemic treatment with dexpramipexole at doses consistent with those already adopted in ALS patients reduces brain infarct size and ameliorates neuroscore in mice subjected to transient or permanent MCAo. Of note, the concentrations of dexpramipexole reached within the ischemic penumbra equal those found neuroprotective in vitro. CONCLUSION AND IMPLICATIONS: For the first time we show that a drug able to boost mitochondrial F1Fo ATP-synthase activity reduces ischemic 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 stroke treatment.
Dexpramipexole improves bioenergetics and outcome in experimental stroke
FERRI, MARTINA;CAMAIONI, Emidio;
2018
Abstract
BACKGROUND AND PURPOSE: To investigate the effects of dexpramipexole, a drug recently tested in ALS patients able to bind F1Fo ATP synthase and increase mitochondrial ATP production, on experimental ischemic brain injury. EXPERIMENTAL APPROACH: 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). The drug's impact on infarct volumes and neurological functions was also evaluated in mice subjected to proximal or distal MCAo. Distribution of dexpramipexole within the ischemic brain was evaluated by means of mass spectrometry imaging. KEY RESULTS: Dexpramipexole boosts 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. The drug also counteracts ATP depletion, mitochondrial swelling, anoxic depolarization, loss of synaptic activity, and neuronal death in hippocampal slices subjected to OGD. Consistently, post-ischemic treatment with dexpramipexole at doses consistent with those already adopted in ALS patients reduces brain infarct size and ameliorates neuroscore in mice subjected to transient or permanent MCAo. Of note, the concentrations of dexpramipexole reached within the ischemic penumbra equal those found neuroprotective in vitro. CONCLUSION AND IMPLICATIONS: For the first time we show that a drug able to boost mitochondrial F1Fo ATP-synthase activity reduces ischemic 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 stroke treatment.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
