Drug development for stroke: importance of protecting cerebral white matter

Dewar, Deborah; Yam, P.S.; McCulloch, James

doi:10.1016/s0014-2999(99)00280-0

Cited by 121 publications

(75 citation statements)

References 59 publications

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“…Unfortunately, most neuroprotection studies do not examine the significance of white matter injury (Coleman and Perry, 2002), which likely has contributed to the failure of clinical trials (Dewar et al, 1999;Stys, 1998). Furthermore, we report that neuronal dendritic structure is markedly affected in both the perihematoma and contralateral striatum, which likely influences behavioral outcome.…”

Section: Discussionmentioning

confidence: 85%

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Progressive Brain Damage and Alterations in Dendritic Arborization after Collagenase-Induced Intracerebral Hemorrhage in Rats

Nguyen¹,

Huynh²,

Sjovold³

et al. 2008

CNR

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Intracerebral hemorrhage (ICH) was widely believed to be a monophasic event whereby cell death occurs from the initial space-occupying effects of the hematoma. However, we now know that secondary degenerative events contribute to delayed cell death, functional impairment and clinical deterioration. In three experiments, we further characterized the long-term maturation of injury in the collagenase model of striatal ICH in rat. First, we quantified the volume of tissue lost from 7 to 60 days showing that tissue loss more than doubled over this time. As the volume of tissue lost does not distinguish gray from white matter damage, gold chloride staining was used in a second experiment in ICH rats that survived 7 or 60 days. The mid-sagittal area of the corpus callosum significantly declined (22%) over this period, whereas the hippocampal and anterior commissures were not affected. A third experiment used the Golgi-Cox stain to examine dendritic arborization of peri-hematoma and contralateral medium spiny neurons of the striatum. We found an early and sustained increase in dendritic arborization in the non-lesioned hemisphere, whereas there was initial atrophy of peri-hematoma striatal neurons that eventually recovered to normal. These findings show that tissue loss, including white matter atrophy, continues over extended periods after ICH making it a potential target for cytoprotective agents. Finally, the dendritic alterations in both ipsi-and contralateral striatal neurons likely influence spontaneous recovery and are potential targets to further improve it.

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Section: Discussionmentioning

confidence: 85%

“…Unfortunately, most ICH studies do not assess white matter injury. Indeed, clinical trials of cytoprotective agents may be less successful because the effect of white matter injury is usually overlooked (Dewar et al, 1999;Stys, 1998).…”

Section: Introductionmentioning

confidence: 99%

Progressive Brain Damage and Alterations in Dendritic Arborization after Collagenase-Induced Intracerebral Hemorrhage in Rats

Nguyen¹,

Huynh²,

Sjovold³

et al. 2008

CNR

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“…Because the normal function of the brain is dependent on the communication between brain regions, the clarification of mechanisms contributing to acute and/or progressive white matter damage is critical to our understanding of brain injury (Goldberg and Ransom, 2003). In this regard, an explanation for the lack of successful human stroke trials is that neuroprotective strategies have primarily targeted gray but not white matter structures (Dewar et al, 1999). Following focal cerebral ischemia, damage to white matter tracts can be observed using a variety of immunocytochemical markers.…”

Section: White Matter Vulnerabilitymentioning

confidence: 99%

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

Bramlett

Dietrich

2004

J Cereb Blood Flow Metab

561

358

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Summary: Current knowledge regarding the pathophysiology of cerebral ischemia and brain trauma indicates that similar mechanisms contribute to loss of cellular integrity and tissue destruction. Mechanisms of cell damage include excitotoxicity, oxidative stress, free radical production, apoptosis and inflammation. Genetic and gender factors have also been shown to be important mediators of pathomechanisms present in both injury settings. However, the fact that these injuries arise from different types of primary insults leads to diverse cellular vulnerability patterns as well as a spectrum of injury processes. Blunt head trauma produces shear forces that result in primary membrane damage to neuronal cell bodies, white matter structures and vascular beds as well as secondary injury mechanisms. Severe cerebral ischemic insults lead to metabolic stress, ionic perturbations, and a complex cascade of biochemical and molecular events ultimately causing neuronal death. Similarities in the pathogenesis of these cerebral injuries may indicate that therapeutic strategies protective following ischemia may also be beneficial after trauma. This review summarizes and contrasts injury mechanisms after ischemia and trauma and discusses neuroprotective strategies that target both types of injuries.

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“…It has been reported that more than 90% of brain tissue in rodents is composed of gray matter, whereas in human, gray matter makes up about 50% of the brain. 79 Even in the most homogeneous population of cortical stroke patients, the damage to white matter in humans will be significantly larger than in rodent models. This is not necessarily important, but is a reason to be cautious in extrapolation of rodent model results to humans, particularly for drugs that have differential effects in white versus gray mater.…”

Section: Problems That May Have Caused the Failure Of Past Clinical Tmentioning

confidence: 99%

Neuroprotection for ischemic stroke: Two decades of success and failure

Al-Khoury

Zivin

2004

Neurotherapeutics

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Summary: Alteplase (rt-PA) is the first therapy successfully developed for acute stroke therapy. The success of rt-PA spurred development of new avenues for acute stroke management. For the last two decades, a great deal of attention has been paid to neuroprotective therapies. Initial preclinical studies demonstrated numerous drugs are effective for treating acute stroke in animal models; however, subsequent clinical trials have been frustrating, and none of the agents has proven effective. The various outcomes of preclinical and clinical trials have been the subject of much discussion. In this article, we review some key neuroprotective trials and the possible reasons for their failures. By identifying the discrepancies between preclinical studies and clinical trials, we may be able to set guidelines for future effective trials.

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Drug development for stroke: importance of protecting cerebral white matter

Cited by 121 publications

References 59 publications

Progressive Brain Damage and Alterations in Dendritic Arborization after Collagenase-Induced Intracerebral Hemorrhage in Rats

Progressive Brain Damage and Alterations in Dendritic Arborization after Collagenase-Induced Intracerebral Hemorrhage in Rats

Pathophysiology of Cerebral Ischemia and Brain Trauma: Similarities and Differences

Neuroprotection for ischemic stroke: Two decades of success and failure

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