Blockade of hippocampal bradykinin B1 receptors improves spatial learning and memory deficits in middle-aged rats

Bitencourt, Rafael Mariano de; Souza, Ana Cristina Guerra; Bicca, Maíra A.; Pamplona, Fabrício A.; Mello, Nelson de; Passos, Giselle F.; Medeiros, Rodrigo; Takahashi, Reinaldo Ν.; Calixto, João B.; Prediger, Rui Daniel

doi:10.1016/j.bbr.2016.08.041

Cited by 14 publications

(14 citation statements)

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“…Recently, it has been indicated that bradykinin released by KKS plays an important role in the central nervous system (31). Brain inflammation aggravates the pathology of AD, and bradykinin B1 receptors play a regulatory role in brain inflammation and in amyloid deposition of AD in mice.…”

Section: Discussionmentioning

confidence: 99%

Effects of rivastigmine hydrogen tartrate and donepezil hydrochloride on the cognitive function and mental behavior of patients with Alzheimer's disease

Zhang

Wang

et al. 2020

Exp Ther Med

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The present study aimed to examine the effects of rivastigmine hydrogen tartrate and donepezil hydrochloride on the cognitive function and mental behavior of patients with Alzheimer's disease (AD). For this purpose, a total of 126 patients with AD admitted to Luoyang Central Hospital from January, 2018 to December, 2018 were enrolled. Patients were divided into different groups according to the treatment they selected. Patients treated with single-agent donepezil were separated into a monotherapy group (n=56), and patients receiving donepezil plus rivastigmine were placed in the combination group (n=70). Before and after treatment, the cognitive functions, mental behavior and quality of life of the patients in the two groups were respectively evaluated by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), the Mini-Mental State Examination (MMSE), the Blessed-Roth Dementia Scale (BRDS) and the QOL-AD. In addition, the serum bradykinin level was detected by enzyme-linked immunosorbent assay. Following treatment, the MMSE score, BRDS, ADAS-Cog and QOL-AD scores were improved compared with those before treatment (P<0.05). However, following treatment, the 4 scores in the combination group were significantly higher than those in the monotherapy group (P<0.05). No significant differences were observed in the incidence of adverse reactions between the 2 groups (P>0.05). Following treatment, the bradykinin level in both groups was significantly decreased (P<0.05), although the decrease in the combination group was more significant than that in the monotherapy group (P<0.05). On the whole, the findings of the present study indicate that rivastigmine hydrogen tartrate used in combination with donepezil hydrochloride relieves the symptoms and improves the quality of life of patients with AD more effectively, which may be related to the reduction of the bradykinin level in these patients.

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Section: Discussionmentioning

confidence: 99%

Effects of rivastigmine hydrogen tartrate and donepezil hydrochloride on the cognitive function and mental behavior of patients with Alzheimer's disease

Zhang

Wang

et al. 2020

Exp Ther Med

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“…Pharmacological blockade of both BRs in transgenic mice over-expressing amyloid precursor protein or mice infused with Aβ has been shown to improve learning and memory formation. B 1 R blockade mitigated cognitive deficits by B 1 R antagonist des-Arg9[Leu8]-bradykinin in Aβ-treated mice (Prediger et al, 2008) and in rat (Bitencourt et al, 2017), and by B 1 R antagonist SSR240612 in Tg-SwDI mice of AD (Lacoste et al, 2013). B 2 R blockade by HOE 140 protected against cognitive impartment in Aβ-infused mice (Prediger et al, 2008; Bicca et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…B 1 R is involved in inflammation in the central nervous system mainly through the activation of microglia (Asraf et al, 2017) and astrocytes (Lacoste et al, 2013). However, the effects of bradykinin inhibition on microglia and astrocytes have been inconsistent, both suppression (Bitencourt et al, 2017) and stimulation (Asraf et al, 2016) of neuroinflammation has been reported, or showed no effect (Asraf et al, 2016). Using measurements of Iba1 immunoreactivity in few selected animals from each group, we found no effect of chronic oral noscapine treatment on microglia activation.…”

Section: Discussionmentioning

confidence: 99%

fMRI Reveals Mitigation of Cerebrovascular Dysfunction by Bradykinin Receptors 1 and 2 Inhibitor Noscapine in a Mouse Model of Cerebral Amyloidosis

Kindler

Waag

et al. 2019

Front. Aging Neurosci.

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Functional magnetic resonance imaging (fMRI) techniques can be used to assess cerebrovascular dysfunction in Alzheimer’s disease, an important and early contributor to pathology. We hypothesized that bradykinin receptor inhibition alleviates the vascular dysfunction in a transgenic arcAβ mouse model of cerebral amyloidosis and that fMRI techniques can be used to monitor the treatment response. Transgenic arcAβ mice, and non-transgenic littermates of 14 months-of-age were either treated with the bradykinin receptors 1 and 2 blocker noscapine or received normal drinking water as control over 3 months (n = 8–11/group) and all mice were assessed using fMRI at the end of the treatment period. Perfusion MRI using an arterial spin labeling technique showed regional hypoperfusion in arcAβ compared to non-transgenic controls, which was alleviated by noscapine treatment. Similarly, measuring cerebral blood volume changes upon pharmacological stimulation using vessel dilator acetazolamide revealed recovery of regional impairment of cerebral vascular reactivity in arcAβ mice upon noscapine treatment. In addition, we assessed with immunohistochemistry beta-amyloid (Aβ) and inflammation levels in brain sections. Immunohistological stainings for Aβ deposition (6E10) and related microgliosis (Iba1) in the cortex and hippocampus were found comparable between noscapine-treated and untreated arcAβ mice. In addition, levels of soluble and insoluble Aβ38, Aβ40, Aβ42 were found to be similar in brain tissue homogenates of noscapine-treated and untreated arcAβ mice using electro-chemiluminescent based immunoassay. In summary, bradykinin receptors blockade recovered cerebral vascular dysfunction in a mouse model of cerebral amyloidosis. fMRI methods revealed the functional deficit in disease condition and were useful tools to monitor the treatment response.

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“…Studies pharmacologically targeting the two receptors also revealed differential effects with B1R expression strongly responsive to inflammation (Sriramula and Lazartigues, 2017) and to changes in the environment (Ongali et al, 2003, Arganaraz et al, 2004. Furthermore, blockade of B1R in rats led to the improvement of cognitive function and agerelated cognitive decline (Prediger et al, 2008, Bitencourt et al, 2017. B2R is crucial in long-term facilitation of angiogenesis and neurogenesis (Xia et al, 2006, Trujillo et al, 2012 playing a protective role against cell-death (Arganaraz et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Bradykinin B2 receptor is essential to running-induced cell proliferation in the adult mouse hippocampus

et al. 2018

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Physical exercise is a strong external effector that induces precursor cell proliferation in the adult mouse hippocampus. Research into mechanisms has focused on central changes within the hippocampus and we have established that serotonin is the signaling factor that transduces physical activity into adult neurogenesis. Less focus has been given on potential peripheral signals that may cause pro-mitotic running effects. Vasoactive kinin peptides are important for blood pressure regulation and inflammatory processes to maintain cardiovascular homeostasis. Acting via the two receptors termed B1 (B1R) and B2R, the peptides also function in the brain. In particular, studies attribute B2R a role in cell proliferation and differentiation into neurons in vitro. Here, we determined B1R and B2R mRNA expression levels in the adult mouse hippocampus and prefrontal cortex in vivo, and in response to running exercise. Using mice depleted in either or both receptors, B1-knockout (KO), B2KO and B1/2KO we observed changes in running performance overnight and in running distances. However, voluntary exercise led to the known pro-mitotic effect in the dentate gyrus of B1KO mice while it was attenuated in B2KO accompanied by an increase in microglia cells. Our data identify B2R as an important factor in running-induced precursor cell proliferation.

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Blockade of hippocampal bradykinin B1 receptors improves spatial learning and memory deficits in middle-aged rats

Cited by 14 publications

References 30 publications

Effects of rivastigmine hydrogen tartrate and donepezil hydrochloride on the cognitive function and mental behavior of patients with Alzheimer's disease

Effects of rivastigmine hydrogen tartrate and donepezil hydrochloride on the cognitive function and mental behavior of patients with Alzheimer's disease

fMRI Reveals Mitigation of Cerebrovascular Dysfunction by Bradykinin Receptors 1 and 2 Inhibitor Noscapine in a Mouse Model of Cerebral Amyloidosis

Bradykinin B2 receptor is essential to running-induced cell proliferation in the adult mouse hippocampus

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