Dataset Information

Dexpramipexole improves bioenergetics and outcome in experimental stroke.

ABSTRACT:

Background and purpose

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.

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). 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.

Key results

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.

Conclusion and implications

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.

Linked articles

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.

SUBMITTER: Muzzi M

PROVIDER: S-EPMC5758384 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Publications

Dexpramipexole improves bioenergetics and outcome in experimental stroke.

Muzzi Mirko M Gerace Elisabetta E Buonvicino Daniela D Coppi Elisabetta E Resta Francesco F Formentini Laura L Zecchi Riccardo R Tigli Laura L Guasti Daniele D Ferri Martina M Camaioni Emidio E Masi Alessio A Pellegrini-Giampietro Domenico E DE Mannaioni Guido G Bani Daniele D Pugliese Anna M AM Chiarugi Alberto A

British journal of pharmacology 20170512 2

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>The effects of dexpramipexole on bioenergetics, Ca<sup>2+</sup> fluxes, electrophysiological functions and death were evaluated in primary neural cultures and hippocampal slices exposed to ox ...[more]

PMID: 28320070

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Project description:Background and purposeIschemic stroke significantly perturbs neuronal homeostasis leading to a cascade of pathologic events causing brain damage. In this study, we assessed acute stroke outcome after chemogenetic inhibition of forebrain excitatory neuronal activity.MethodsWe generated hM4Di-TG transgenic mice expressing the inhibitory hM4Di, a Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic receptor, in forebrain excitatory neurons. Clozapine-N-oxide (CNO) was used to activate hM4Di DREADD. Ischemic stroke was induced by transient occlusion of the middle cerebral artery. Neurologic function and infarct volumes were evaluated. Excitatory neuronal suppression in the hM4Di-TG mouse forebrain was assessed electrophysiologically in vitro and in vivo, based on evoked synaptic responses, and in vivo based on occurrence of potassium-induced cortical spreading depolarizations.ResultsDetailed characterization of hM4Di-TG mice confirmed that evoked synaptic responses in both in vitro hippocampal slices and in vivo motor cortex were significantly reduced after CNO-mediated activation of the inhibitory hM4Di DREADD. Further, CNO treatment had no obvious effects on physiology and motor function in either control or hM4Di-TG mice. Importantly, hM4Di-TG mice treated with CNO at either 10 min before ischemia or 30 min after reperfusion exhibited significantly improved neurologic function and smaller infarct volumes compared to CNO-treated control mice. Mechanistically, we showed that potassium-induced cortical spreading depression episodes were inhibited, including frequency and duration of DC shift, in CNO-treated hM4Di-TG mice.ConclusionsOur data demonstrate that acute inhibition of a subset of excitatory neurons after ischemic stroke can prevent brain injury and improve functional outcome. This study, together with the previous work in optogenetic neuronal modulation during the chronic phase of stroke, supports the notion that targeting neuronal activity is a promising strategy in stroke therapy.

Dataset Information

Dexpramipexole improves bioenergetics and outcome in experimental stroke.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Linked articles

Publications

Dexpramipexole improves bioenergetics and outcome in experimental stroke.

Similar Datasets

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