IMM-H004 therapy for permanent focal ischemic cerebral injury via CKLF1/CCR4-mediated NLRP3 inflammasome activation
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INTRODUCTION
Stroke, particularly acute ischemic stroke, is a devastating and debilitating disease and is the third leading cause of death in the Western world.1 Currently, thrombolytic therapy remains the common therapy for patients with acute ischemic stroke, and recombinant tissue plasminogen activator (tPA) is the only Food and Drug Administration (FDA)-approved drug for clinical application. However, few patients (2%−7%) benefit from tPA because this drug must be injected within 4.5 hours post onset of
Animals
Male wild-type (WT) adult SD rats (6–8 weeks, 250–280 g) were obtained from VITAL RIVER Laboratories, Beijing, China. CKLF1−/− SD rats (250–280 g) were obtained from the Key Laboratory of Human Disease Comparative Medicine, NHFPC, Institute of Laboratory Animal Science, Peking Union Medicine College, Chinese Academy of Medical Sciences, Beijing, China. All rats were housed under standard conditions. The experimental protocols and animal care were performed according to the National Research
IMM-H004 protects against ischemic stroke-induced brain injury
The protective effects of IMM-H004 on ischemic stroke-induced brain injury were determined by traditional methods. IMM-H004 and urokinase (10,000 UI/kg) treatment pronouncedly reduced the brain infarct size and attenuated the neurologic deficits compared with the pMCAO group (Fig 1, C and D).
Nissl staining indicated a sharp decrease of normal neurons in the CA1 hippocampus, cortex, and striatum after pMCAO operation, with relict neurons manifested by karyopyknosis, anachromasis, nucleoli
DISCUSSION
Cerebral ischemia initiates a complex series of pathophysiological events, which evolve over time and space. These cascade reactions cause progressive and massive neural damage and death, leading to severe functional impairment. Therapeutic strategies that target the acute phase of stroke remain ineffective in patients besides thrombolysis. Thus, it becomes essential to develop new approaches that target new therapeutic windows to significantly improve the processes of functional recovery.
Acknowledgments
Conflicts of Interest: All authors have read the journal's policy on the disclosure of potential conflicts of interest and have no conflicts to declare.
This work was supported by the Hunan University of Chinese Medicine First-class Disciple Construction Project (201803), Project of NDRC and State Administration of Traditional Chinese Medicine (ZYBZH-Y-HUN-24), Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces (2016TP2008), Open found of Hunan
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2022, European Journal of PharmacologyCitation Excerpt :7-hydroxy-5-methoxy-4-methyl-3-(4-methylpiperazin-1-yl)-2H-chromen-2-one (IMM-H004), a synthetic simple hydroxycoumarin was also shown in multiple studies to protect against cerebral ischemia injury (Sun et al., 2013; Zuo et al., 2015). In a permanent middle cerebral artery occlusion (pMCAO) model (Ai et al., 2019), the administration of IMM-H004 6 h after ischemia provided significant neuroprotection in rats as evidenced by behavioral tests and histologic data (infarction areas, infarct size, edema …). An anti-inflammatory effect was confirmed by a dose dependent decrease in the levels of IL-1β and TNF-α in brain tissues.
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