Myeloperoxidase Propagates Damage and is a Potential Therapeutic Target for Subacute Stroke

Abstract

Few effective treatment options exist for stroke beyond the hyperacute period. Radical generation and myeloperoxidase (MPO) have been implicated in stroke. We investigated whether pharmacologic reduction or gene deletion of this highly oxidative enzyme reduces infarct propagation and improves outcome in the transient middle cerebral artery occlusion mouse model (MCAO). Mice were treated with 4-aminobenzoic acid hydrazide (ABAH), a specific irreversible MPO inhibitor. Three treatment regimens were used: (1) daily throughout the 21-day observational period, (2) during the acute stage (first 24 hours), or (3) during the subacute stage (daily starting on day 2). We found elevated MPO activity in ipsilateral brain 3 to 21 days after ischemia. 4-Aminobenzoic acid hydrazide reduced enzyme activity by 30% to 40% and final lesion volume by 60% (P<0.01). The MPO-knockout (KO) mice subjected to MCAO also showed a similar reduction in the final lesion volume (P<0.01). The ABAH treatment or MPO-KO mice also improved neurobehavioral outcome (P<0.001) and survival (P=0.01), but ABAH had no additional beneficial effects in MPO-KO mice, confirming specificity of ABAH. Interestingly, inhibiting MPO activity during the subacute stage recapitulated most of the therapeutic benefit of continuous MPO inhibition, suggesting that MPO-targeted therapies could be useful when given after 24 hours of stroke onset.

Myeloperoxidase Inhibition Increases Neurogenesis after Ischemic Stroke

“…Another group of mice was treated with normal saline as control on the same schedule. The optimal ABAH dose has been determined in prior studies and results in an ∼40% attenuation of MPO activity in vivo (Forghani et al, 2012(Forghani et al, , 2015. To determine cell proliferation, the thymidine analog, bromodeoxyuridine (BrdU; 50 mg/kg in 0.9% saline, i.p.…”

“…The number of mice used for each group was calculated to achieve a power of 90% (30% difference in mean and S.D. of 15% based on our prior experience using this model; Forghani et al, 2015), resulting in n 5 3 per group. …”

“…MPO itself can also function to recruit neutrophils (Klinke et al, 2011), propagating the inflammatory cascade. Elevated MPO expression has been found to persist for 21 days after stroke in a mouse model , and inhibiting MPO activity markedly decreased infarct size, even when given during the subacute stage of stroke (Forghani et al, 2015).…”

Spinal Cord Inflammation: Molecular Imaging after Thoracic Aortic Ischemia Reperfusion Injury

“…Results are representative of five independent experiments in each group. (37). Key advantages of MR imaging are detailed structural imaging and more advanced sequences such as DW imaging.…”

“…Our results showed that MPO activity paralleled the decrease in viable motor neurons in the spinal cord thoracolumbar segment after TAR. However, given the deleterious roles of MPO and its products in the pathogenesis of different diseases (37,38), it is possible MPO not only is a bystander reporter but also directly participates in causing motor neuron injury. While or blood-spinal barrier.…”