Dexpramipexole Attenuates White Matter Injury to Facilitate Locomotion and Motor Coordination Recovery via Reducing Ferroptosis after Intracerebral Hemorrhage

Abstract

Deciphering the factors causing damage to white matter fiber bundles and exploring new strategies to alleviate white matter injury (WMI) is a promising treatment to improve neurological impairments after intracerebral hemorrhage (ICH). Ferroptosis usually occurs at perihematomal region and contributes to neuronal death due to reactive oxygen species (ROS) production. Dexpramipexole (DPX) easily crosses the blood brain barrier (BBB) and exerts antioxidative properties by reducing ROS production, while the role of DPX in ferroptosis after ICH remains elusive. Here, our results indicated that ferroptosis played a significant role in WMI resulting from iron and ROS accumulation around hematoma. Further evidence demonstrated that the administration of DPX decreased iron and ROS deposition to inhibit ferroptosis at perihematomal site. With the inhibition of ferroptosis, WMI was alleviated at perihematomal site, thereafter promoting locomotion and motor coordination recovery in mice after ICH. Subsequently, the results showcased that the expression of glutathione peroxidase 4 (GPX4) and ferroptosis suppressing protein 1 (FSP1) was upregulated with the administration of DPX. Collectively, the present study uncovers the underlying mechanism and elucidates the therapeutic effect of DPX on ICH, and even in other central nervous system (CNS) diseases with the presence of ferroptosis.

Kv1.3 blockade alleviates white matter injury through reshaping M1/M2 phenotypes after intracerebral hemorrhage

“…First, the Kv1.3 blockade promotes the regenerative ability resulting from neural progenitor cell (NPC), as previous study has indicated the administration of Kv1.3 inhibitor promotes NPC proliferation after brain injury [14]. Second, the administration of PAP-1 promotes oligodendrocyte progenitor cell (OPC) proliferation and differentiation into oligodendrocyte, which are responsible for myelination in the CNS [7], through increasing AKT activation [45]. Third, the application of PAP-1 increased the neurotrophic factors (including NGF and BDNF) around hematoma, which support neuron survival [46].…”

“…The reason for the long-term disability possibly ascribes to the white matter injury (WMI) in basal ganglia [3]. Our previous studies have illustrated that the integrity of white matter ber bundles is a promotor for functional recovery [4][5][6], and a series of strategies, such as the inhibition of ferroptosis with the administration of dexpramipexole (DPX) [7], upregulation of brain-derived neurotrophic factor (BDNF) by lithium [8], and inactivation of microglia into M1 phenotype using ambroxol [9], have been corroborated to accelerate functional recovery through mitigating WMI after ICH.…”

Elucidating the progress and impact of ferroptosis in hemorrhagic stroke

“…A recent study showed in the FSP1/CoQ10 antioxidant system that the level of FSP1 was significantly reduced in the brain tissue surrounding hematomas in ICH mice, which could be treated with the drug dexpramipexole to reverse this harmful change ( Wang B. et al, 2022 ). However, the expression pattern and the underlying mechanism with the potential role of CoQ10 have not been adequately investigated.…”

“…Subsequently, they further systematically presented ample evidence of ferroptosis in oligodendrocytes after ICH ( Shen et al, 2022 ). Dexpramipexole has also been reported to attenuate white matter damage caused by oligodendrocyte ferroptosis in mice after ICH, thereby improving spatial localization and motor function ( Wang B. et al, 2022 ). Moreover, ferroptosis has also been reported to be involved in white matter damage after spinal cord injury, which can be suppressed by the application of Fer-1 ( Chen et al, 2022 ).…”

Dexpramipexole ameliorates cognitive deficits in sepsis-associated encephalopathy through suppressing mitochondria-mediated pyroptosis and apoptosis

“…Pharmacokinetic studies have demonstrated that DPX is clinically safe and well-tolerated [22]. DPX can easily cross the blood-brain barrier and accumulate within the brain [23][24][25]. Moreover, DPX has been found to improve mitochondrial efficiency, decrease ROS production, suppress apoptosis and increase cell survival, thus exerting neuroprotective effects in animal models of stroke and progressive multiple sclerosis [26,27].…”