Therapeutic effect of tPA in ischemic stroke is enhanced by its combination with normobaric oxygen and hypothermia or ethanol

Ji, Zhili; Liu, Kayin; Cai, Lining; Peng, Changya; Xin, Ruiqiang; Gao, Zhi; Zhao, Ethan; Rastogi, Radhika; Han, Wei; Rafols, José A.; Xu, Geng; Ding, Yuchuan

doi:10.1016/j.brainres.2015.08.019

Cited by 15 publications

(18 citation statements)

References 44 publications

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“…While combined treatment approaches are also utilized in other central nervous system disorders, such as stroke (Gisvold et al, 1984; Liu et al, 2010; Wang et al, 2012; Ji et al, 2015; Schuch et al, 2016) and spinal cord injury (Koopmans et al, 2009; Tanabe et al, 2009; Lee et al, 2012; Wilems et al, 2015), the aim of this review is to highlight the current state of combinational treatment approaches for neurobehavioral and cognitive recovery in experimental TBI. The review, which is the first, and currently the only, to comprehensively assess the effects of combination therapies on behavioral outcomes after TBI, is based on studies that were found on a PubMed search in March 2016 using the key phrase “combination AND therapy AND traumatic AND brain AND injury” that produced 529 papers.…”

Section: Introductionmentioning

confidence: 99%

Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?

Kline

Leary

Radabaugh

et al. 2016

Progress in Neurobiology

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Traumatic brain injury (TBI) is a significant health care crisis that affects two million individuals in the United Sates alone and over ten million worldwide each year. While numerous monotherapies have been evaluated and shown to be beneficial at the bench, similar results have not translated to the clinic. One reason for the lack of successful translation may be due to the fact that TBI is a heterogeneous disease that affects multiple mechanisms, thus requiring a therapeutic approach that can act on complementary, rather than single, targets. Hence, the use of combination therapies (i.e., polytherapy) has emerged as a viable approach. Stringent criteria, such as verification of each individual treatment plus the combination, a focus on behavioral outcome, and post-injury vs. pre-injury treatments, were employed to determine which studies were appropriate for review. The selection process resulted in 37 papers that fit the specifications. The review, which is the first to comprehensively assess the effects of combination therapies on behavioral outcomes after TBI, encompasses five broad categories (inflammation, oxidative stress, neurotransmitter dysregulation, neurotrophins, and stem cells, with and without rehabilitative therapies). Overall, the findings suggest that combination therapies can be more beneficial than monotherapies as indicated by 46% of the studies exhibiting an additive or synergistic positive effect versus on 19% reporting a negative interaction. These encouraging findings serve as an impetus for continued combination studies after TBI and ultimately for the development of successful clinically relevant therapies.

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Section: Introductionmentioning

confidence: 99%

Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?

Kline

Leary

Radabaugh

et al. 2016

Progress in Neurobiology

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“…MH exerts an inhibitory effect on brain cell apoptosis through caspase-3 mechanisms in rats with MCAO/R [ 20 , 22 ]. We found that MH significantly reduced the number of caspase-3 + cells in the sub-granular zone of the injured hemisphere at all time points after the onset of ischemia in rats with MCAO/R.…”

Section: Discussionmentioning

confidence: 99%

“…Caspase-3, a member of the family of cysteine proteases, is a major marker of neuronal apoptosis [ 17 ] in ischemic brain damage [ 18 , 19 ]. MH exerts an inhibitory effect on neuronal apoptosis through caspase-3 mechanisms in the ischemic brain during adult focal cerebral ischemia/reperfusion injury [ 20 - 22 ]. However, studies investigating the effect of MH upon caspase-3 immunopositive cells (caspase-3 + cells) or neuronal apoptosis in the sub-granular zone remain sparse [ 10 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Mild hypothermia modulates the expression of nestin and caspase-3 in the sub-granular zone and improves neurological outcomes in rats with ischemic stroke

Zhou

Wang

et al. 2017

Oncotarget

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We assessed neurological outcomes, infarct volume, and the expression of nestin and caspase-3 in the hippocampal dentate gyrus following middle cerebral artery occlusion (MCAO) followed by reperfusion, with mild hypothermia (MH) treatment at the onset of ischemia in a MCAO rat model. Reperfusion began 2 hours after the MCAO model was set-up. MH treatment began at the onset of ischemia and was maintained for 4 hours. We evaluated neurological deficit score, brain infarct volumes, along with the immunohistochemical staining of nestin and caspase-3 in the sub-granular zone of the injured hemisphere on the 1st, 3rd, 7th, and 14th day after the onset of ischemia. Correlations between the number of nestin-positive (nestin+) cells, caspase-3-positive (caspase-3+) cells with infarct volume, as well as neurological deficit scores, were evaluated by linear regression. MH significantly promoted survival, reduced mortality, improved neurological deficit score, reduced brain infarct volume, increased the number of neural stem/progenitor cells and inhibited neuronal apoptosis in the sub-granular zone of the injured hemisphere. The number of nestin+ cells correlated with neurological deficit score in the normothermic group, and with infarct volume in the hypothermia group except for the first day after the onset of ischemia. The number of caspase-3+ cells correlated with the neurological deficit score but not infarct volume. The neuroprotective effects of MH may be mediated by modulating neural stem/progenitor cells and neuronal apoptotic cells in the sub-granular zone of the injured hemisphere during cerebral ischemia/reperfusion injury.

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“…Delayed administration of minocycline alone or reduced hyperglycolysis and modulated pyruvate dehydrogenase complex in thromboembolic cerebral ischemia (Cai et al, 2016a, b, c). Of note, therapeutic effect of tPA in ischemic stroke was enhanced in combination with NBO and hypothermia (Ji et al, 2015); therefore, it is reasonable to combine NBO and MH after acute ischemia stroke.…”

Section: Controversy Of Delayed Hypothermia Treatmentmentioning

confidence: 99%

Oxygen or cooling, to make a decision after acute ischemia stroke

Liu

Jin

2016

Med Gas Res

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The presence of a salvageable penumbra, a region of ischemic brain tissue with sufficient energy for short-term survival, has been widely agreed as the premise for thrombolytic therapy with tissue plasminogen activator (tPA), which remains the only United States Food and Drug Administration (FDA) approved treatment for acute ischemia stroke. However, the use of tPA has been profoundly constrained due to its narrow therapeutic time window and the increased risk of potentially deadly hemorrhagic transformation (HT). Blood brain barrier (BBB) damage within the thrombolytic time window is an indicator for tPA-induced HT and both normobaric hyperoxia (NBO) and hypothermia have been shown to protect the BBB from ischemia/reperfusion injury. Therefore, providing the O2 as soon as possible (NBO treatment), freezing the brain (hypothermia treatment) to slow down ischemia-induced BBB damage or their combined use may extend the time window for the treatment of tPA. In this review, we summarize the protective effects of NBO, hypothermia or their use combined with tPA on ischemia stroke, based on which, the combination of NBO and hypothermia may be an ideal early stroke treatment to preserve the ischemic penumbra. Given this, there is an urge for large randomized controlled trials to address the effect.

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Therapeutic effect of tPA in ischemic stroke is enhanced by its combination with normobaric oxygen and hypothermia or ethanol

Cited by 15 publications

References 44 publications

Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?

Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?

Mild hypothermia modulates the expression of nestin and caspase-3 in the sub-granular zone and improves neurological outcomes in rats with ischemic stroke

Oxygen or cooling, to make a decision after acute ischemia stroke

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