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Chlorpromazine and promethazine reduces Brain injury through RIP1-RIP3 regulated activation of NLRP3 inflammasome following ischemic stroke.
- Source :
-
Neurological research [Neurol Res] 2021 Aug; Vol. 43 (8), pp. 668-676. Date of Electronic Publication: 2021 Apr 08. - Publication Year :
- 2021
-
Abstract
- Objectives: Stroke is an important cause of death and disability. Recent evidence suggests that post-stroke inflammation is an important factor in stroke pathology and a root cause of its lasting consequences. Phenothiazine drugs, like chlorpromazine and promethazine (C + P), induce hypothermia and have been shown to play a major role in neuroprotection. In the present study, we investigated this neuroprotective mechanism by assessing the anti-inflammatory effect of these drugs. Methods: Adult Sprague-Dawley rats underwent 2 h of middle cerebral artery occlusion (MCAO) followed by 6 or 24 h of reperfusion, with or without C + P (8 mg/kg). Infarct volumes, neurological deficits, along with mRNA and protein quantities of receptor-interacting protein 1 (RIP1), receptor-interacting protein 3 (RIP3), NLRPyrin domain containing 3 (NLRP3), and interleukin-1β (IL-1β) were assessed, as well as the infiltration of neutrophils and macrophages. Results: C + P induced hypothermia that significantly reduced RIP1, RIP3, NLRP3 and IL-1β expression, infarction, and immune cell infiltration, while C + P treatment with temperature control at 37°C induced lesser effect. Conclusion: These findings suggest that the anti-inflammatory effect of C + P may be dependent on drug-induced hypothermia and regulation of the NLRP3 inflammasome via the RIP1/RIP3 complex. Future investigations are needed regarding C + P as potential treatment of ischemic stroke.
- Subjects :
- Animals
Brain Injuries metabolism
Brain Injuries pathology
Drug Therapy, Combination
Ischemic Stroke metabolism
Ischemic Stroke pathology
Male
NLR Family, Pyrin Domain-Containing 3 Protein biosynthesis
Rats
Rats, Sprague-Dawley
Receptor-Interacting Protein Serine-Threonine Kinases biosynthesis
Brain Injuries drug therapy
Chlorpromazine administration & dosage
Ischemic Stroke drug therapy
NLR Family, Pyrin Domain-Containing 3 Protein antagonists & inhibitors
Promethazine administration & dosage
Receptor-Interacting Protein Serine-Threonine Kinases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1743-1328
- Volume :
- 43
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Neurological research
- Publication Type :
- Academic Journal
- Accession number :
- 33829970
- Full Text :
- https://doi.org/10.1080/01616412.2021.1910904