Abstract
ATP-binding cassette (ABC) transporters prevent the access of pharmacological compounds to the ischemic brain, thereby impeding the efficacy of stroke therapies. ABC transporters can be deactivated by selective inhibitors, which potently increase the brain accumulation of drugs. Concerns have been raised that long-term ABC transporter deactivation may promote neuronal degeneration and, under conditions of ischemic stroke, compromise neurological recovery. To elucidate this issue, we exposed male C57BL/6 mice to transient intraluminal middle cerebral artery occlusion (MCAO) and examined the effects of the selective ABCB1 inhibitor tariquidar (8 mg/kg/day) or ABCC1 inhibitor MK-571 (10 mg/kg/day), which were administered alone or in combination with each other over up to 28 days, on neurological recovery and brain injury. Mice were sacrificed after 14, 28, or 56 days. The Clark score, RotaRod, tight rope, and open field tests revealed reproducible motor-coordination deficits in mice exposed to intraluminal MCAO, which were not influenced by ABCB1, ABCC1, or combined ABCB1 and ABCC1 deactivation. Brain volume, striatum volume, and corpus callosum thickness were not altered by ABCB1, ABCC1 or ABCB1, and ABCC1 inhibitors. Similarly, neuronal survival and reactive astrogliosis, evaluated by NeuN and GFAP immunohistochemistry in the ischemic striatum, were unchanged. Iba1 immunohistochemistry revealed no changes of the overall density of activated microglia in the ischemic striatum of ABC transporter inhibitor treated mice, but subtle changes of microglial morphology, that is, reduced microglial cell volume by ABCB1 deactivation after 14 and 28 days and reduced microglial ramification by ABCB1, ABCC1 and combined ABCB1 and ABCC1 deactivation after 56 days. Endogenous neurogenesis, assessed by BrdU incorporation analysis, was not influenced by ABCB1, ABCC1 or combined ABCB1 and ABCC1 deactivation. Taken together, this study could not detect any exacerbation of neurological deficits or brain injury after long-term ABC transporter deactivation in this preclinical stroke model.
Highlights
MATERIALS AND METHODSDespite considerable progress in acute stroke treatment, i.e., intravenous thrombolysis and mechanical thrombectomy, stroke remains the leading cause of long-term disability
Intraluminal middle cerebral artery occlusion (MCAO) resulted in a Laser Doppler flow (LDF) decrease to ∼20% of baseline, followed by the rapid LDF restitution after reperfusion that was not influenced by ABCB1 deactivation with tariquidar, ABCC1 deactivation with MK-571 or combined ABCB1 and ABCC1 deactivation with tariquidar and MK-571 (F = 0.01; p = 0.99) (Figure 1A)
Endogenous neurogenesis has previously been shown to be reduced in the subgranular zone of the dentate gyrus in otherwise healthy Abcb1−/−, but not Abcc1−/− mice (Schumacher et al, 2012)
Summary
MATERIALS AND METHODSDespite considerable progress in acute stroke treatment, i.e., intravenous thrombolysis and mechanical thrombectomy, stroke remains the leading cause of long-term disability. The ABC transporter ABCB1, which is preferentially expressed on the luminal endothelial membrane and carries drugs in direction from the brain to blood, is upregulated (Spudich et al, 2006), whereas ABCC1, which is preferentially expressed on the abluminal endothelial membrane and carries drugs in the opposite direction from the blood to brain, is downregulated after intraluminal middle cerebral artery occlusion (MCAO) (Kilic et al, 2008). We did not notice any aggravation of brain injury following ABCB1 or ABCC1 deactivation in the acute stroke phase, i.e., during the first 72 h post-MCAO (Spudich et al, 2006; Kilic et al, 2008) This observation did not rule out the exacerbation of brain injury in the subsequent post-acute phase, where major efforts are currently made establishing neurorestorative treatments. To explore possible injury-promoting effects, we studied consequences of a long-term delivery of the ABCB1 and ABCC1 inhibitors tariquidar and MK-571 on post-ischemic neurological deficits, delayed neurodegeneration and brain tissue remodeling in mice exposed to intraluminal MCAO
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