Therapeutic efficacy of matrix metalloproteinase-12 suppression on neurological recovery after ischemic stroke: Optimal treatment timing and duration.
Therapeutic efficacy of matrix metalloproteinase-12 suppression on neurological recovery after ischemic stroke: Optimal treatment timing and duration.
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DOI：
10.3389/fnins.2022.1012812
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发表时间：
2022
影响因子：
4.3
通讯作者：
Veeravalli, Krishna Kumar
中科院分区：
文献类型：
--
作者：
Challa, Siva Reddy;Nalamolu, Koteswara Rao;Fornal, Casimir A.;Wang, Billy C.;Martin, Ryan C.;Olson, Elsa A.;Ujjainwala, Ammar L.;Pinson, David M.;Klopfenstein, Jeffrey D.;Veeravalli, Krishna Kumar
我们最近发现，缺血后诱导脑中基质金属蛋白酶-12（MMP-12）降解紧密连接蛋白，增加MMP-9和TNFα表达，并导致血脑屏障（BBB）破坏、细胞凋亡、脱髓鞘和梗死体积发展。本研究的目的是（1）确定通过shRNA介导的基因沉默抑制MMP-12对神经/功能恢复的影响，（2）确定MMP-12 shRNA治疗的最佳时机，以提供最大的治疗益处，（3）比较急性与慢性MMP-12抑制的有效性，（4）评价治疗结果中潜在的性别相关差异。对年轻的雄性和雌性Sprague-Dawley大鼠进行短暂的大脑中动脉闭塞和再灌注。向大鼠组群施用MMP-12 shRNA或乱序shRNA序列（对照）表达质粒（lmg/kg; i. v.）配制成纳米颗粒。在再灌注后的指定时间点，对来自不同组的大鼠进行一系列神经学测试，以评估其反射、平衡、感觉和运动功能。MMP-12的抑制促进了中风诱导的雄性和雌性大鼠的神经恢复，尽管这种效果在雌性大鼠中不太明显。再灌注后立即治疗导致感觉和运动功能的恢复比延迟治疗更好。慢性MMP-12抑制既不增强也不减弱急性MMP-12抑制的治疗效果，表明单剂量的质粒可能就足够了。我们的结论是，抑制MMP-12缺血性卒中后是一个有前途的治疗策略，促进神经功能的恢复。
We recently showed that the post-ischemic induction of matrix metalloproteinase-12 (MMP-12) in the brain degrades tight junction proteins, increases MMP-9 and TNFα expression, and contributes to the blood-brain barrier (BBB) disruption, apoptosis, demyelination, and infarct volume development. The objectives of this study were to (1) determine the effect of MMP-12 suppression by shRNA-mediated gene silencing on neurological/functional recovery, (2) establish the optimal timing of MMP-12shRNA treatment that provides maximum therapeutic benefit, (3) compare the effectiveness of acute versus chronic MMP-12 suppression, and (4) evaluate potential sex-related differences in treatment outcomes. Young male and female Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion and reperfusion. Cohorts of rats were administered either MMP-12shRNA or scrambled shRNA sequence (control) expressing plasmids (1 mg/kg; i.v.) formulated as nanoparticles. At designated time points after reperfusion, rats from various groups were subjected to a battery of neurological tests to assess their reflex, balance, sensory, and motor functions. Suppression of MMP-12 promoted the neurological recovery of stroke-induced male and female rats, although the effect was less apparent in females. Immediate treatment after reperfusion resulted in a better recovery of sensory and motor function than delayed treatments. Chronic MMP-12 suppression neither enhanced nor diminished the therapeutic effects of acute MMP-12 suppression, indicating that a single dose of plasmid may be sufficient. We conclude that suppressing MMP-12 after an ischemic stroke is a promising therapeutic strategy for promoting the recovery of neurological function.
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影响因子：
5.9
作者：
Nalamolu KR;Chelluboina B;Fornal CA;Challa SR;Pinson DM;Wang DZ;Klopfenstein JD;Veeravalli KK
通讯作者：
Veeravalli KK
影响因子：
4.6
作者：
Chelluboina B;Warhekar A;Dillard M;Klopfenstein JD;Pinson DM;Wang DZ;Veeravalli KK
通讯作者：
Veeravalli KK
影响因子：
6.9
作者：
Nalamolu KR;Challa SR;Fornal CA;Grudzien NA;Jorgenson LC;Choudry MM;Smith NJ;Palmer CJ;Pinson DM;Klopfenstein JD;Veeravalli KK
通讯作者：
Veeravalli KK
影响因子：
5.3
作者：
Lee, SR;Kim, HY;Lo, EH
通讯作者：
Lo, EH
影响因子：
14.5
作者：
Lee, Jee Y.;Kim, Hwang S.;Yune, Tae Y.
通讯作者：
Yune, Tae Y.