title: Angiotensin Converting Enzyme Inhibitors Ameliorate Brain Inflammation Associated with Microglial Activation: Possible Implications for Alzheimer's Disease.
abstract: Angiotensin converting enzyme (ACE) converts Angiotensin I to a potent vasoconstrictor angiotensin II (ANG II). ACE inhibitors (ACEIs) are widely used for the management of hypertension. All components of the renin-angiotensin system (RAS) have also been identified in the brain. In addition to cytokines, neuromodulators such as ANG II can induce neuroinflammation. Moreover, in Alzheimer's disease (AD) models, where neuroinflammation occurs and is thought to contribute to the propagation of the disease, increased levels of ANG II and ACE have been detected. However, the specific effect of ACEIs on neuroinflammation and AD remains obscure. The present study suggests that captopril and perindopril, centrally active ACEIs, may serve as modulators for microglial activation associated with AD. Our in vitro study investigated the effect of both ACEIs on nitric oxide (NO), tumor necrosis factor- α (TNF-α) release and inducible NO synthase (iNOS) expression in lipopolysaccharide (LPS)-induced BV2 microglia. Exposure of BV2 microglia to ACEIs significantly attenuated the LPS-induced NO and TNF-α release. In vivo, short term intranasal administration of perindopril or captopril to 5 Familial AD (5XFAD) mice significantly reduced amyloid burden and CD11b expression (a microglial marker) or only CD11b expression respectively, in the cortex of 5XFAD. Long-term intranasal administration of captopril to mice reduced amyloid burden with no effect on CD11b expression. We provide evidence that intranasal delivery of ACEI may serve as an efficient alternative for their systemic administration, as it results in the attenuation of microglial accumulation and even the reduction of Amyloid β (Aβ) plaques.
authors: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, P.O, B 653, Beer-Sheva, Israel.
authors: Nofar
authors: N
authors: Torika
authors: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, P.O, B 653, Beer-Sheva, Israel.
authors: Keren
authors: K
authors: Asraf
authors: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, P.O, B 653, Beer-Sheva, Israel.
authors: Ella
authors: E
authors: Roasso
authors: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, P.O, B 653, Beer-Sheva, Israel.
authors: Abraham
authors: A
authors: Danon
authors: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, P.O, B 653, Beer-Sheva, Israel. fleisher@bgu.ac.il.
authors: Sigal
authors: S
authors: Fleisher-Berkovich
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002460:Cell Line; D004660:Encephalitis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors
keywords: Amyloid β; Angiotensin converting enzyme (ACE); Captopril; Microglia; Neuroinflammation; Perindopril