Critical appraisal of neuroprotection trials in head injury: What have we learned?

Tolias, Christos M.; Bullock, M. Ross

doi:10.1007/bf03206568

Cited by 36 publications

(54 citation statements)

References 75 publications

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“…All of these individual differences have contributed to the failure to translate a successful pharmacological intervention to date, 7,8 and to the resultant reticence in the pharmacological industry to venture into acute brain injury trials. Nonetheless, many of these shortcomings can be easily addressed with appropriate preclinical screening and clinical trial design.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, the complexity and heterogeneity of clinical TBI, and in particular the multifactorial nature of the secondary injury process, constitute one of the most significant hurdles to trial success. 8,9 Given the multifactorial nature of the secondary injury process, it is unlikely that targeting a single factor will result in a significant improvement in outcome. Conversely, simultaneously targeting several injury factors may be the most likely therapeutic approach to improve outcome.…”

Section: Introductionmentioning

confidence: 99%

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Multifunctional Drugs for Head Injury

2009

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Summary: Traumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide in individuals under the age of 45 years, and, despite extensive efforts to develop neuroprotective therapies, there has been no successful outcome in any trial of neuroprotection to date. In addition to recognizing that many TBI clinical trials have not been optimally designed to detect potential efficacy, the failures can be attributed largely to the fact that most of the therapies investigated have been targeted toward an individual injury factor. The contemporary view of TBI is that of a very heterogenous type of injury, one that varies widely in etiology, clinical presentation, severity, and pathophysiology. The mechanisms involved in neuronal cell death after TBI involve an interaction of acute and delayed anatomic, molecular, biochemical, and physiological events that are both complex and multifaceted. Accordingly, neuropharmacotherapies need to be targeted at the multiple injury factors that contribute to the secondary injury cascade, and, in so doing, maximize the likelihood of a successful outcome. This review focuses on a number of such multifunctional compounds that have shown considerable success in experimental studies and that show maximum promise for success in clinical trials.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multifunctional Drugs for Head Injury

2009

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“…However, their complex interactions have made it difficult to determine which pathways should be addressed therapeutically in TBI. To date, most approaches to the treatment of TBI that target a single injury mechanism have failed in clinical trials (Ikonomidou and Turski, 2002;Tolias and Bullock, 2004;McKee et al, 2005). Consequently, it has been suggested that "recognition of multiple cell death pathways should lead to new treatment strategies, including both combination drug treatment and drugs that affect multiple components of the secondary injury cascade" (Faden, 2002).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Caspase-Mediated Apoptosis by Peroxynitrite in Traumatic Brain Injury

Lau¹,

Arundine²,

Sun³

et al. 2006

J. Neurosci.

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In traumatic brain injury (TBI), neurons surviving the primary insult may succumb through poorly understood secondary mechanisms. In vitro, cortical neurons exposed to stretch injury exhibited enhanced vulnerability to NMDA, apoptotic-like DNA fragmentation, peroxynitrite (PN) formation, and cytoplasmic cytochrome c accumulation. Surprisingly, caspase-3 activity was undetectable by both immunoblotting and fluorogenic activity assays. Therefore, we hypothesized that PN directly inhibits caspases in these neurons. Consistent with this, stretch injury in cultured neurons elicited tyrosine nitration of procaspase-3, but not caspase-9 or Apaf-1, suggesting a direct interaction of PN with caspase-3. In an ex vivo system, PN inhibited the activity of caspase-3, and this inhibition was reversible with the addition of the sulfhydryl reducing agent dithiothreitol, indicating that PN inhibits caspases by cysteinyl oxidation. Moreover, in cultures, the PN donor 3-morpholinosydnonimine (SIN-1) blocked staurosporine-induced caspase-3 activation and its downstream effects including PARP-1 [poly-(ADP-ribose) polymerase-1] cleavage and phosphotidylserine inversion, suggesting that peroxynitrite can inhibit caspase-3-mediated apoptosis. To examine these mechanisms in vivo, rats were exposed to a lateral fluid percussion injury (FPI). FPI caused increased neuronal protein nitration that colocalized with TUNEL staining, indicating that PN was associated with neurodegeneration. Caspase-3 activity was inhibited in brain lysates harvested after FPI and was restored by adding dithiothreitol. Our data show that caspase-mediated apoptosis is inhibited in neurons subjected to stretch in vitro and to TBI in vivo, mostly because of cysteinyl oxidation of caspase-3 by PN. However, this is insufficient to prevent cell death, indicating that the TBI therapy may, at a minimum, require a combination of both anti-apoptotic and anti-oxidant strategies.

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“…Pharmacologic strategies have included blocking calcium channels and the NMDA receptor and inhibiting lipid peroxidation, free radical generation and inflammation, among many others (see Maas, 2001, Maas et al, 2005. Unfortunately, to date, no neuroprotective agent has shown efficacy in a clinical trial in TBI patients (reviewed in Maas et al, 1999, Narayan et al, 2002, Tolias and Bullock, 2004. We propose that a more mechanistic understanding of cognitive recovery after TBI will prove to be very important in evaluating new compounds intended for future clinical trials.…”

Section: Discussionmentioning

confidence: 99%

“…These long-lasting cognitive impairments are among the most debilitating outcomes in patients, yet, to date, no treatment can prevent or counteract these effects in TBI patients (Maas, 2001, Narayan et al, 2002, Tolias and Bullock, 2004.…”

Section: Introductionmentioning

confidence: 99%

Neurotrophin-mediated neuroprotection of hippocampal neurons following traumatic brain injury is not associated with acute recovery of hippocampal function

et al. 2007

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Traumatic brain injury (TBI) causes selective hippocampal cell death which is believed to be associated with the cognitive impairment observed in both clinical and experimental settings. The endogenous neurotrophin NT-4/5, a TrkB ligand, has been shown to be neuroprotective for vulnerable CA3 pyramidal neurons after experimental brain injury. In this study, infusion of recombinant NT-4/5 increased survival of CA2/3 pyramidal neurons to 71% after lateral fluid percussion injury in rats, compared to 55% in vehicle-treated controls. The functional outcome of this NT-4/5-mediated neuroprotection was examined using three hippocampal-dependent behavioral tests. Injury-induced impairment was evident in all three tests, but interestingly, there was no treatment-related improvement in any of these measures. Similarly, injury-induced decreased excitability in the Schaffer collaterals was not affected by NT-4/5 treatment. We propose that a deeper understanding of the factors that link neuronal survival to recovery of function will be important for future studies of potentially therapeutic agents.

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Critical appraisal of neuroprotection trials in head injury: What have we learned?

Cited by 36 publications

References 75 publications

Multifunctional Drugs for Head Injury

Multifunctional Drugs for Head Injury

Inhibition of Caspase-Mediated Apoptosis by Peroxynitrite in Traumatic Brain Injury

Neurotrophin-mediated neuroprotection of hippocampal neurons following traumatic brain injury is not associated with acute recovery of hippocampal function

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