Microglial Activation Is Modulated by Captopril: in Vitro and in Vivo Studies.

Keren Asraf,Sigal Fleisher-Berkovich,Nofar Torika,Ron N Apte

doi:10.3389/fncel.2018.00116

Keren Asraf, Sigal Fleisher-Berkovich + Show 2 more

Open Access

https://doi.org/10.3389/fncel.2018.00116

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Abstract

The renin-angiotensin system (RAS) is an important peripheral system involved in homeostasis modulation, with angiotensin II (Ang II) serving as the main effector hormone. The main enzyme involved in Ang II formation is angiotensin-converting enzyme (ACE). ACE inhibitors (ACEIs) such as captopril (Cap) are predominantly used for the management of hypertension. All of the components of the RAS have also been identified in brain. Centrally located hormones such as Ang II can induce glial inflammation. Moreover, in Alzheimer’s disease (AD) models, where glial inflammation occurs and is thought to contribute to the propagation of the disease, increased levels of Ang II and ACE have been detected. Interestingly, ACE overexpression in monocytes, migrating to the brain was shown to prevent AD cognitive decline. However, the specific effects of captopril on glial inflammation and AD remain obscure. In the present study, we investigated the effect of captopril, given at a wide concentration range, on inflammatory mediators released by lipopolysaccharide (LPS)-treated glia. In the current study, both primary glial cells and the BV2 microglial cell line were used. Captopril decreased LPS-induced nitric oxide (NO) release from primary mixed glial cells as well as regulating inducible NO synthase (iNOS) expression, NO, tumor necrosis factor-α (TNF-α) and induced interleukin-10 (IL-10) production by BV2 microglia. We further obtained data regarding intranasal effects of captopril on cortical amyloid β (Aβ) and CD11b expression in 5XFAD cortex over three different time periods. Interestingly, we noted decreases in Aβ burden in captopril-treated mice over time which was paralleled by increased microglial activation. These results thus shed light on the neuroprotective role of captopril in AD which might be related to modulation of microglial activation.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disease considered as the most common type of dementia worldwide (Stansley et al, 2012; Kettenmann et al, 2013)
We investigated the effects of captopril, a potent ACE inhibitors (ACEIs), administered across a wide range of concentrations, on inflammatory mediators released by lipopolysaccharide (LPS)-induced glia
The microglial inflammatory response can be mimicked by the use of LPS endotoxin, which triggers microglia to secrete a wide variety of inflammatory cytokines (Pardon, 2015)

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disease considered as the most common type of dementia worldwide (Stansley et al, 2012; Kettenmann et al, 2013). It is well accepted that glial-mediated inflammation contributes to the progression of the disease (Griffin, 2006; Tejera and Heneka, 2016). As activated microglia are responsible for brain homeostasis, they mediate the innate immune response in the central nervous system (CNS; Tejera and Heneka, 2016). Glial cytokine production plays crucial roles in the chronic and self-sustained inflammatory cycles seen in AD, subsequently leading to neuronal dysfunction (Griffin, 2006; Glass et al, 2010). High levels of pro-inflammatory cytokines, such as interleukin-1β (IL1β) and tumor necrosis factor-α (TNF-α), were observed in the cerebrospinal fluid (CSF) and brains of AD patients (Tarkowski et al, 1999; López González et al, 2016). A direct interaction between Aβ proteins and TNF-a type 1 receptor (TNFR1) was reported to stimulate inflammatory cascades leading to neuronal apoptosis (Li et al, 2004)

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