Heat shock protein 70 upregulation by geldanamycin reduces brain injury in a mouse model of intracerebral hemorrhage.
This study investigated the effect of geldanamycin post-treatment on the development of secondary brain injury and neurological deficits in a mouse model of intracerebral hemorrhage. CD-1 mice received stereotactic injection of collagenase type VII into the right basal ganglia. Treatment groups were administered 1 mg/kg (low dose) or 10 mg/kg (high dose) of geldanamycin. Mice were euthanized at two time-points: 24 h or 72 h. Blood-brain-barrier permeability, brain edema, and neurobehavioral deficits were assessed. Additionally, the effects of geldanamycin on heat shock protein 27 and 72; tumor necrosis factor-alpha and interleukin 1 beta expressions were evaluated. High dose geldanamycin significantly attenuated blood-brain barrier disruption and brain edema after intracerebral hemorrhage. Neurobehavioral outcomes were significantly improved in some parameters by high dose treatment. Molecular results showed a marked increase in heat shock protein 72 expression in ipsilateral brain of geldanamycin treated groups with a reduction in the pro-inflammatory tumor necrosis factor-alpha.


CONCLUSIONS
Geldanamycin post-treatment is neuroprotective in the mouse model of intracerebral hemorrhage. Geldanamycin administration results in reduction of inflammation, preservation of blood-brain-barrier and amelioration of neurobehavioral deficits after an insult possibly by upregulation of heat shock protein 72.
Manaenko
Anatol
A
Department of Physiology, Loma Linda University, Loma Linda, CA 92350, USA.
Fathali
Nancy
N
Chen
Hank
H
Suzuki
Hidenori
H
Williams
Shammah
S
Zhang
John H
JH
Tang
Jiping
J
D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D001930:Brain Injuries / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D002543:Cerebral Hemorrhage / Q000150:complications / Q000378:metabolism* / Q000517:prevention & control*; D004195:Disease Models, Animal; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D050884:HSP72 Heat-Shock Proteins / Q000096:biosynthesis; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D011897:Random Allocation; D015854:Up-Regulation / Q000502:physiology*
D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D050884:HSP72 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C001277:geldanamycin