Neuroprotective Effects of Kinin B2 Receptor in Organotypic Hippocampal Cultures of Middle-Aged Mice

Abstract

Aging is a multifactorial phenomenon that results in several changes at cellular and molecular levels and is considered the main risk factor for some neurodegenerative diseases. Several evidence show the participation of the kallikrein-kinin system (KKS) in neurodegeneration and this system has been associated with inflammation and immunogenic responses in the central and peripheral systems by the activation of the B1 and B2 receptors. Previous work by our group showed that bradykinin (BK) and the B2 receptor played a possible role in neuroprotection. Therefore, the objective of this study was to evaluate the participation of B2 receptors in cell viability, neuroinflammatory response and neuroplasticity in organotypic hippocampal cultures (OHCs) of 6- and 12-month-old mice. It was observed that activation of the B2 receptor by bradykinin decreased the inflammatory response and increased plasticity in 12-month-old slices. Conversely, there was an increase in the inflammatory response and a decrease in neural plasticity in the 6-month-old slices. In both ages, an increase in cell viability was observed. This data suggests that the function of the kinin B2 receptor in the hippocampus is modulated by age, providing neuroprotective action in old age.

Kinin B2 Receptor Activation Prevents the Evolution of Alzheimer’s Disease Pathological Characteristics in a Transgenic Mouse Model

“…In order to evaluate the secreted substances associated with the activation of the BKB2R, we adopted the organotypic hippocampal culture (OHC) model using a reduced number of animals (four per group/treatment). Our laboratory has developed a method that allows the maintenance of healthy hippocampal slices of adult animals (12 months old) for a long period of time [ 12 ]. To confirm the viability and good maintenance of the hippocampal slices from the WT and TG animals over the 28 days in vitro (28DIV), we stained the slices with propidium iodide to quantify cell death.…”

“…However, the role of the BKB1R cannot be discarded; Sanden et al demonstrated that BKB1R is upregulated after lipopolysaccharide (LPS) injection, resulting in an increase in TNFα and IFNɣ [ 33 ]. Another study recently published by our group demonstrated the importance of animals’ age with respect to the neuroprotective action of bradykinin and BKB2R [ 12 ]. In this study, a decrease in inflammatory markers was observed after treatment with BK only in 12-month-old animals; in 6-month-old animals, kinin receptor activation increased inflammatory markers [ 12 ].…”

“…Another study recently published by our group demonstrated the importance of animals’ age with respect to the neuroprotective action of bradykinin and BKB2R [ 12 ]. In this study, a decrease in inflammatory markers was observed after treatment with BK only in 12-month-old animals; in 6-month-old animals, kinin receptor activation increased inflammatory markers [ 12 ]. Due to technical limitations in obtaining acceptable thinner slices from organotypic hippocampal culture, the present work has the limitation of not showing microglia activation by immunohistochemistry.…”

“…Organotypic hippocampal culture was prepared according to previous studies from our group [ 12 , 49 ]. Briefly, mice were anesthetized, euthanized by decapitation, their brains were rapidly removed, and 300 µm sagittal slices (6–9 per brain) were taken using a vibratome (Leica VT1000S, Wetzlar, Germany) and dissected to isolate the hippocampus.…”

“…These data point to BKB2R activation as a potential therapeutic target in AD. Moreover, another study by our group showed that the B2R only played a neuroprotective and anti-inflammatory role in organotypic hippocampal slices after BK stimulation in middle-aged adult mice (12 months old), but not in samples from young adult animals (6 months), thus showing its age-modulated neuroprotective role [ 12 ]. However, the role of the BKB2R in Alzheimer’s disease has not yet been fully elucidated.…”