HAMI 3379, a CysLT2R antagonist, dose- and time-dependently attenuates brain injury and inhibits microglial inflammation after focal cerebral ischemia in rats. (16th April 2015)

• Record Type: Journal Article
• Authors: Shi, Q.J.; Wang, H.; Liu, Z.X.; Fang, S.H.; Song, X.M.; Lu, Y.B.; Zhang, W.P.; Sa, X.Y.; Ying, H.Z.; Wei, E.Q.
• Is Part Of: Neuroscience. Volume 291(2015)
• Page Start: 53
• Page End: 69
• Publication Date: 2015-04-16
• Subjects: Blood–brain barrier BBB -- CSF cerebrospinal fluid -- CysLT1R cysteinyl leukotriene receptor 1 -- CysLT2R cysteinyl leukotriene receptor 2 -- CysLTs cysteinyl leukotrienes -- DMSO dimethyl sulfoxide -- GFAP glial fibrillary acidic protein -- Iba-1 ionized calcium-binding adapter molecule 1 -- i.c.v. Intracerebroventricular -- IFN-γ interferon-γ -- IL- interleukin- -- IgG immunoglobulin G -- LTC4 leukotriene C4 -- LTD4 leukotriene D4 -- LTE4 leukotriene E4 -- MCA middle cerebral artery -- MCAO middle cerebral artery occlusion -- MPO myeloperoxidase -- NC negative control -- NeuN neuronal nuclear antigen -- OGD/R oxygen-glucose deprivation/recovery -- shRNA short hairpin RNA -- TH1 T-helper 1 -- TH2 T-helper 2 -- TNF-α tumor necrosis factor-α -- TTC 2, 3, 5-triphenyltetrazolium chloride; HAMI 3379 -- cysteinyl leukotriene receptor 2 (CysLT2R) -- antagonist -- cerebral ischemia -- microglia -- inflammation; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2015.02.002
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: We determined the neuroprotective effect of the CysLT2 R antagonist HAMI 3379. HAMI 3379 dose- and time-dependently protects rats from ischemic stroke. The effective dose is 0.1 ∼ 0.4 mg/kg and the therapeutic window is 1 h. HAMI 3379 has the effects on ischemic brain injury similar to pranlukast. It selectively attenuates microglia-related post-ischemic inflammation. Abstract: Cysteinyl leukotrienes (CysLTs) induce inflammatory responses by activating their receptors, CysLT1 R and CysLT2 R. We have reported that CysLT2 R is involved in neuronal injury, astrocytosis, and microgliosis, and that intracerebroventricular (i.c.v.) injection of the selective CysLT2 R antagonist HAMI 3379 protects against acute brain injury after focal cerebral ischemia in rats. In the present study, we clarified features of the protective effect of intraperitoneally-injected HAMI 3379 in rats. We found that HAMI 3379 attenuated the acute brain injury 24 h after middle cerebral artery occlusion (MCAO) with effective doses of 0.1–0.4 mg/kg and a therapeutic window of ∼1 h. It attenuated the neurological deficits, and reduced infarct volume, brain edema, and neuronal loss and degeneration 24 and 72 h after MCAO. RNA interference with i.c.v. injection of CysLT2 R short hairpin RNA (shRNA) attenuated the acute injury as well. Also, HAMI 3379 inhibited release of the cytokines IL-1β, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) into the serum and cerebrospinal fluid 24 h after MCAO. Moreover, HAMI 3379 ameliorated the microglial activation and neutrophil accumulation in the ischemic regions, but did not affect astrocyte proliferation 72 h after MCAO. In comparison, the CysLT1 R antagonist pranlukast did not affect microglial activation and IFN-γ release, but inhibited astrocyte proliferation and reduced serum IL-4. Thus, we conclude that HAMI 3379 has a protective effect on acute and subacute ischemic brain injury, and attenuates microglia-related inflammation. CysLT2 R antagonist(s) alone or in combination with CysLT1 R antagonists may be a novel class of therapeutic agents in the treatment of ischemic stroke.