Geldanamycin Reduced Brain Injury in Mouse Model of Intracerebral Hemorrhage
We investigated the effect of the heat shock protein inducer geldanamycin on the development of secondary brain injury after ICH in mice. The effect of the drug at two different concentrations was evaluated at two time points: 24 and 72 h after ICH induct
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Abstract We investigated the effect of the heat shock protein inducer geldanamycin on the development of secondary brain injury after ICH in mice. The effect of the drug at two different concentrations was evaluated at two time points: 24 and 72 h after ICH induction. In the first part of this study, a total of 30 male CD-1 mice were randomly divided into four groups: one sham group and three ICH groups. ICH animals received either an intraperitoneal injection of vehicle or geldanamycin (1 or 10 mg/kg). Neurological deficits and brain water content were evaluated 24 h after ICH. In the second part of this study, the effect of a high concentration of geldanamycin was evaluated 72 h after ICH. Neurological deficits were evaluated by the Garcia neuroscoring, wire hanging and beam balance tests. For estimation of brain water content, the “wet/dry weight” method was used. We demonstrated that administration of geldanamycin (10 mg/kg) ameliorated ICH-induced increase of brain water content significantly in both parts of the study. Geldanamycin improved the neurological outcome according to performance on Garcia and beam balance tests in the 72 h part of this study. Geldanamycin-induced induction of heat shock protein after ICH has a neuroprotective effect and may be a therapeutic target for ICH. Keywords Geldanamycin · HSP · ICH Neuroprotection
Introduction Intracerebral hemorrhage (ICH) is a devastating clinical event with greater than 40% initial mortality, leaving many of the survivors permanently disabled. Currently, there is
A. Manaenko, N. Fathali, S. Williams, T. Lekic, J.H. Zhang, and J. Tang (*) Department of Physiology and Pharmacology, Loma Linda University, School of Medicine, Loma Linda, CA 92350, USA e-mail: [email protected]
neither an effective therapy to increase survival after intracerebral hemorrhage nor a treatment to improve the quality of life of survivors [1]. There are biphasic effects of intracerebral hemorrhage upon brain tissue. Initial injury is in response to the expanding hematoma imposing sheer forces and mass effect upon the cerebral tissues [2]. Intracerebral bleeding leads to increased intracranial pressures and could lead to transtentorial herniation secondary to the mass effect [3]. A later phase involves hematoma-induced neuronal and glial apoptotic cell death at the surrounding parenchymal rim [4], inflammation and progressive rupture of the blood-brainbarrier, and rising brain edema [5]. Geldanamycin belongs to the family of ansamycin antibiotics. Biochemical and structural studies have demonstrated that geldanamycin binds specifically to the ATP pocket of the constitutively induced heat shock protein (HSP) 90 and inhibits its chaperone activity and its ability to bind to target proteins [6]. HSP 90 affects multiple signal transduction pathways [7] and has been shown to regulate more than 100 proteins involved in cellular signaling [7]. HSP 90 is a negative regulator of heat shock factor 1 (HSF 1). The binding between HSP 90 and geldanamycin makes HSP 90 unable to associate with
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