Medical Therapy for Intracerebral Hematoma With the γ-Aminobutyric Acid-A Agonist Muscimol

Lyden, Patrick D.; Jackson-Friedman, Catherine; Lonzo-Doktor, Lisa

doi:10.1161/01.str.28.2.387

Cited by 33 publications

(17 citation statements)

References 27 publications

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“…Even though collagenase does not discriminate among different brain tissues, it produces massive bleeding and mortality, similar to that in human ICH. This model has been used extensively in investigations of ICH (Brown et al, 1995;DeBow et al, 2003;Del Bigio et al, 1996;Elger et al, 1994;Lyden et al, 1997;MacLellan et al, 2002;Matsushita et al, 2000;Rosenberg and Navratil, 1997;Rosenberg et al, 1992), including studies on the long-term deficits after collagenase-induced ICH (Chesney et al, 1995). Another animal model used to determine ICH pathophysiology and to evaluate therapeutic treatment (Andaluz et al, 2002) is the direct injection of autologous blood into the rat caudate nucleus (Nath et al, 1986), a model used in numerous studies (Bullock et al, 1984;Huang et al, 2002;Jiang et al, 2002;Mendelow, 1993;Nath et al, 1987;Thulborn et al, 1990;Xue and Del Bigio, 2000;Wu et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

MMP-9 Deficiency Enhances Collagenase-Induced Intracerebral Hemorrhage and Brain Injury in Mutant Mice

Tang

Zhou

et al. 2004

J Cereb Blood Flow Metab

160

141

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Summary:Matrix metalloproteinase-9 (MMP-9) participates in the disregulation of blood-brain barrier during hemorrhagic transformation, and exacerbates brain injury after cerebral ischemia. However, the consequences of long-term inhibition or deficiency of MMP-9 activity (which might affect normal collagen or matrix homeostasis) remains to be determined. The authors investigated how MMP-9 gene deficiency enhances hemorrhage and increases mortality and neurologic deficits in a collagenase-induced intracerebral hemorrhage (ICH) model in MMP-9-knockout mice. MMP-9-knockout and corresponding wild-type mice at 20 to 35 weeks were used to model an aged population (because advanced age is a significant risk factor in human ICH). Collagenase VII-S (0.5 L, 0.075 U) was injected into the right basal ganglia in mice and mortality, neurologic deficits, brain edema, and hemorrhage size measured. In addition, MMP-9 activity, brain collagen content, blood coagulation, cerebral arterial structure, and expressions of several MMPs were examined. Increased hemorrhage and brain edema that correlated with higher mortality and neurologic deficits were found in MMP-9-knockout mice. No apparent structural changes were observed in cerebral arteries, even though brain collagen content was reduced in MMP-9-knockout mice. MMP-9-knockout mice did exhibit an enhanced expression of MMP-2 and MMP-3 in response to ICH. The results indicate that a deficiency of MMP-9 gene in mutant mice increases collagenase-induced hemorrhage and the resulting brain injury. The intriguing relationship between MMP-9 deficiency and collagenase-induced ICH may reflect the reduction in collagen content and an enhanced expression of MMP-2 and MMP-3. Key Words: MMP-9-Intracerebral hemorrhage-Collagenase-Edema-Blood-brain barrier-Coagulation.Spontaneous intracerebral hemorrhage (ICH) is one of the most serious stroke events, and results in high mortality and morbidity in patients (Bernardini and DeShaies, 2001;Panagos et al., 2002;Woo and Broderick, 2002). Mortality in ICH is often as high as 50% within the first month after ICH, with 50% of these deaths occurring within 48 hours (Broderick, 1993). The mechanisms of ICH-induced early brain injury (e.g. brain edema) have been investigated (Altumbabic et al., 1998;Del Bigio et al., 1999;Xi et al., 2002); however, the complete etiology of early brain injury in ICH is incompletely understood.Matrix metalloproteinases (MMPs) are involved in the pathogenesis of cerebral vascular disorders, particularly the formation and rupture of aneurysms. For example, pro-MMP-2 has been implicated as a significant component within arterial walls of intracerebral aneurysms that leads to subarachnoid hemorrhage (Todor et al., 1998). Other studies also support elevated MMP (elastase and collagenase) activity in ruptured vessels in subarachnoid hemorrhage but not in unruptured aneurysms (Gaetani et al., 1999). MMPs are also involved in the hemorrhagic transformation after cerebral ischemia, especially after thrombolysis (Hosomi et al., 2001;M...

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Section: Discussionmentioning

confidence: 99%

MMP-9 Deficiency Enhances Collagenase-Induced Intracerebral Hemorrhage and Brain Injury in Mutant Mice

Tang

Zhou

et al. 2004

J Cereb Blood Flow Metab

160

141

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“…However, the functional significance of the hypermetabolic areas is still uncertain because MK-801 did not improve behavioral outcome in the collagenase model of ICH. 25 It is possible that the glutamate antagonists were not given early enough in that previous study or that the actions of glutamate affect early edema and survival rather than behavioral outcome, possibilities that need future testing. Finally, the factors that stimulate glutamate release are unclear from this study and could include cytokines, inflammatory cells, heme itself, glutamate from blood, and other factors.…”

Section: Clinical Relevancementioning

confidence: 99%

Glutamate Receptor Blockade Attenuates Glucose Hypermetabolism in Perihematomal Brain After Experimental Intracerebral Hemorrhage in Rat

Ardizzone

Wagner

et al. 2004

Stroke

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Background and Purpose-Intracerebral hemorrhage has no effective treatment. The delayed appearance of edema, apoptosis, and inflammation in perihematomal brain suggests that these events may be targets for therapeutic intervention. To develop successful treatments, we must learn more about the effects of hemorrhage on brain tissue. In this study, we investigated the acute metabolic effects of intrastriatal hemorrhage in rat brain. Methods-Lysed blood or saline (50 L each) was injected into the striatum of male Sprague-Dawley rats. The rats recovered for 1 to 72 hours before injection of [ 14 C]-2-deoxyglucose (intraperitoneally) 30 minutes before decapitation. Animals were pretreated with the N-methyl-D-aspartate (NMDA) and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonists dizolcilpine maleate (MK-801; 1 mg/kg) or 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline (NBQX; 30 mg/kg), or saline vehicle. Additional animals received intrastriatal injections of glutamate (1.0 mmol/L), NMDA (1.0 mmol/L), or AMPA (0.1 mmol/L) in the place of blood. Semiquantitative autoradiographs from the brains were analyzed to determine the effects of hemorrhage on relative glucose metabolism. Results-We found an acute phase of increased [14 C]-2-deoxyglucose uptake in the perihematomal region that peaks 3 hours after lysed blood injection. Saline injections had no effect on striatal glucose utilization. The increased [14 C]-2-deoxyglucose uptake produced by the hemorrhages was blocked by pretreatment with MK-801 and NBQX. Glutamate injections alone had no effect on striatal metabolism, whereas NMDA and AMPA injections increased [ 14 C]-2-deoxyglucose uptake. Conclusions-The data imply that glutamate activation of NMDA or AMPA receptors increases glucose metabolism in perihematomal brain at early times after intracerebral hemorrhage. This may provide a possible target for the treatment of intracerebral hemorrhage.

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“…Compared with prior studies with other agents, however, the efficacy of ganaxolone is only modest. 18 Since pregnanolone and the lower dose of ganaxolone were not beneficial in the bioassay, they Figure 3. Effect of ganaxolone on retention of the escape platform location.…”

Section: Discussionmentioning

confidence: 99%

“…To measure the effect of treatment on clinical outcome, we adapted the quantal bioassay used in ischemia studies, 17,18 comparing the behavioral ratings with the doses of collagenase injected in each group. At lower collagenase doses all subjects are normal, at high doses all subjects are abnormal, and with intermediate doses a fraction of the animals are abnormal.…”

Section: Methodsmentioning

confidence: 99%

“…The quantal bioassay method has proven useful in numerous previous investigations. 17,18 The independent samples t test was used to compare ED 50 values between groups because no multigroup ANOVA method has been developed yet; Bonferroni correction was used to compensate for multiple comparisons. To rigorously compare treatments, separate control groups were used for each drug tested; this procedure reduces the likelihood of spurious findings due to variation of the control ED 50 over time.…”

Section: Methodsmentioning

confidence: 99%

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Effect of Ganaxolone in a Rodent Model of Cerebral Hematoma

Lyden¹,

Shin²,

Jackson-Friedman³

et al. 2000

Stroke

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Background and Purpose-Therapy with ␥-aminobutyric acid (GABA) agonists appears to improve outcome after experimental hematoma but with unacceptable side effects. We looked to synthetic GABA agonists, or positive GABA modulators, widely developed as anticonvulsants and anxiolytics, to find compounds that may be effective. Ganaxolone is a synthetic neuroactive steroid that positively modulates GABA. We sought to determine whether ganaxolone was beneficial using a model of intracerebral hematoma. Methods-We stereotaxically injected varying doses of bacterial collagenase into the caudate nucleus of rats to induce blood-brain barrier failure and hematoma formation. Four hours later, we administered intravenously 15 or 30 mg/kg ganaxolone (nϭ23 each group), 20 mg/kg pregnanolone (nϭ21), or vehicle (nϭ30). Forty-eight hours after collagenase injection, we rated each animal using a standard rodent neurological examination. The ratings were compared with the amounts of injected collagenase using the quantal bioassay procedure. Other sets of animals were tested later for visuospatial learning. Brains were then prepared for histomorphometry, and brain volumes were estimated. Results-We found that ganaxolone 30 mg/kg significantly increased the ED 50 in the bioassay, for a potency ratio of 1.8Ϯ0.41 compared with vehicle (PϽ0.05). Ganaxolone 15 mg/kg and pregnanolone did not affect neurological outcome. Ganaxolone 30 mg/kg did not clearly improve visuospatial learning several weeks after hemorrhage. Ganaxolone exhibited a weak effect on cerebral volumes 48 hours after stroke, but 3 months after hemorrhage no such effect could be detected. Conclusions-Ganaxolone improves neurological outcome 48 hours after intracerebral hematoma but not visuospatial learning several weeks after intracerebral hematoma. Histological evidence of damage was reduced at 48 hours but not at 3 months. (Stroke. 2000;31:169-175.)

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Medical Therapy for Intracerebral Hematoma With the γ-Aminobutyric Acid-A Agonist Muscimol

Abstract: We conclude that muscimol significantly improves neurological outcome after intracerebral hematoma.

Cited by 33 publications

References 27 publications

MMP-9 Deficiency Enhances Collagenase-Induced Intracerebral Hemorrhage and Brain Injury in Mutant Mice

MMP-9 Deficiency Enhances Collagenase-Induced Intracerebral Hemorrhage and Brain Injury in Mutant Mice

Glutamate Receptor Blockade Attenuates Glucose Hypermetabolism in Perihematomal Brain After Experimental Intracerebral Hemorrhage in Rat

Effect of Ganaxolone in a Rodent Model of Cerebral Hematoma

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