Dexpramipexole improves bioenergetics and outcome in experimental stroke

Abstract

BACKGROUND AND PURPOSEDexpramipexole, 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 APPROACHThe effects of dexpramipexole on bioenergetics, Ca 2+ 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 RESULTSDexpramipexole increased mitochondrial ATP production in cultured neurons or glia and reduces energy failure, prevents intracellular Ca 2+ 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 IMPLICATIONSDexpramipexole, 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.

Neuroprotection induced by dexpramipexole delays disease progression in a mouse model of progressive multiple sclerosis

“…Further, the ability of dexpramipexole to counteract oligomycin neurotoxicity is in line with the binding of dexpramipexole to the oligomycin sensitivity-conferring protein subunits of the F1Fo ATP synthase (Alavian et al, 2015). Notably, the present study along with prior studies showing the ability of dexpramipexole to protect from hypoxic/ischaemic brain damage , Muzzi, Gerace, et al, 2018 supports the relevance of the "virtual hypoxia" hypothesis to MS progression, as well as that of drugs boosting mitochondrial ATP production. Development of therapeutic agents able to interfere with initial derangement of sodium homeostasis within demyelinating axons and intra-axonal Ca 2+ deregulation might complement not only bioenergetic drugs but also current immunosuppressive strategies.…”

“…Thus, by maintaining a bedside to bench approach that can circumvent drug attrition and accelerate clinical translation to progressive MS patients, we selected dexpramipexole, the R‐enantiomer of the anti‐parkinsonian drug pramipexole, which shows clinically little ability to bind to dopamine receptors (Gribkoff & Bozik, 2008). Remarkably, experimental evidence indicates that dexpramipexole improves mitochondrial efficiency by increasing ATP production in spite of reduced oxygen consumption (Alavian et al, 2012; Muzzi et al, 2018), a key effect that, in principle, might counteract virtual hypoxia in degenerating axons during progressive MS. In keeping with this interpretation, further studies have demonstrated the ability of dexpramipexole to bind specific subunits of F1Fo–ATP synthase and prevent mitochondrial swelling and permeability transition (Alavian et al, 2015; Cassarino, Fall, Smith, & Bennett, 1998; Sayeed et al, 2006).…”

“…This further supports a possible therapeutic effect of dexpramipexole in a demyelinating environment which leads to neuronal and axonal virtual hypoxia. We have recently reported that dexpramipexole increases ATP production in primary cultures of neuronal or glial cells, counteracts anoxic depolarization of brain tissue and protects the rodent brain form both transient and permanent hypoxia/ischaemia (Muzzi, Buonvicino, Urru, Tofani, & Chiarugi, 2018, Muzzi, Gerace, et al, 2018). In addition, dexpramipexole has been recently tested in a large Phase III trial in ALS patients with the aim of supporting survival of motor neurons, however these neurones do not appear to undergo degeneration because of a hypoxic–ischaemic insult.…”

PM2.5 can Promote the Alzheimer's Disease-like Changes through Microglia Related Mechanism in Mice

“…The important roles of hippocampus and cortical in learning and memory have been demonstrated by a lot of investigations [58][59][60], we therefore examined the morphological of neurons in these areas. The neuron damage in hippocampus is a typical pathological characteristic of AD.…”

Inventing new therapies without reinventing the wheel: the power of drug repurposing

“…The authors of the reviews offer their unique perspectives derived from working in diverse environments: pharmaceutical companies with active repurposing programmes (Teva Pharmaceutical Industries) (Cha et al, 2018); governmental research institutions that specialize in this approach of drug development, such as the National Center for Advancing Translational Sciences (Zheng et al, 2018); and academic investigators who have a background of interest in certain pathways or mechanisms where repurposing opportunities present themselves (Berger et al, 2018;Korkmaz-Icöz et al, 2018a). In addition, the themed section compiles a number of original research papers, with new experimental data indicating the potential of repurposing the clinically used PARP inhibitor olaparib for non-oncological indications (Ahmad et al, 2018;Korkmaz-Icöz et al, 2018b); the long-acting PTH analogue LY627-2K (originally in development for osteoporosis) for the therapy of hypoparathyroidism-associated hypocalcaemia (Krishnan et al, 2018); the clinical-stage drug development candidate dexpramipexole for stroke (Muzzi et al, 2018); the 'age-old' antibiotic rifampicin as a neuroprotectant in traumatic brain injury (López-García et al, 2018); various clinical-stage glycogen phosphorylase inhibitors for type I diabetes (Nagy et al, 2018); the FDA-approved food additive β-caryophyllene for the therapy of alcoholic steatohepatitis (Varga et al, 2018); and various non-steroidal anti-inflammatory drugs (e.g. ibuprofen) as potential therapeutics for acute pancreatitis (Bombardo et al, 2018).…”