Changes in hippocampal and cortical B1 bradykinin receptor biological activity in two experimental models of epilepsy

doi:10.1016/S0306-4522(99)00075-5

Neuroscience

Volume 92, Issue 3, June 1999, Pages 1043-1049

https://doi.org/10.1016/S0306-4522(99)00075-5 Get rights and content

Abstract

An increased response to the activation of receptors mediating excitatory effects may be involved in some forms of epilepsy. In this study, it has been tested whether B₁ bradykinin receptors (which mediate excitatory effects in the peripheral nervous system and have little constitutional expression in the central nervous system) may be proposed in this role. Two experimental models of epilepsy (kindling and kainate) have been employed, and glutamate outflow experiments have been performed in hippocampal and cortical slices taken from control, kindled and kainate-treated rats. The endogenous B₁ receptor agonist Lys-des-Arg⁹-bradykinin (10⁻⁷ M) did not affect electrically-evoked glutamate overflow in control animals, but concentration-dependently increased it in kindled rats (maximal effect +40 to +50%) and, to a lesser extent (+20%), in kainate-treated rats. These effects were fully prevented by the selective B₁ receptor antagonist R-715 (10⁻⁶ M), but not by the selective B₂ receptor antagonist Hoe 140 (10⁻⁶ M).

The observed changes in B₁ bradykinin receptor biological activity may play a role in epileptic hyperexcitability.

Section snippets

Preparation of the animals

Male Sprague–Dawley rats (300–350 g; Stefano Morini, Reggio Emilia, Italy) were used for all experiments. The animals were housed under standard conditions: constant temperature (22–24°C) and humidity (55–65%), 12 h dark–light cycle, free access to food and water. Procedures involving animals and their care were carried out in accordance with European Community and national laws and policies. All efforts were made to minimize animal suffering, and to reduce the number of animals used.

Kainate was

Results

Glutamate basal outflow and electrically-evoked overflow from hippocampal slices of control, saline-injected and sham-stimulated (collectively `control') rats were much higher than those measured from cortical slices (Table 1). However, no significant differences were observed in either parameter and in either brain area in slices taken from kindled or kainate-treated rats (Table 1).

The endogenous B₁ bradykinin receptor agonist Lys-des-Arg⁹-bradykinin (0.1 μM) did not modify electrical

Discussion

Two principal findings emerge from this study. (1) The endogenous B₁ bradykinin receptor agonist Lys-des-Arg⁹-bradykinin was found to increase electrical stimulation-evoked glutamate overflow in hippocampal and cortical slices taken from kindled, but not from control, rats; this effect has been pharmacologically characterized as B₁ receptor-mediated. (2) Under the experimental conditions employed, these changes in B₁ bradykinin receptor biological activity were much more pronounced in the

Conclusion

An up-regulation of a B₁ bradykinin receptor-mediated excitatory response has been found in critical areas of the epileptic brain. This is the first report on the involvement of the bradykinin system in epilepsy and, in general, of alterations in B₁ bradykinin receptors in the forebrain. The observation of these phenomena in a chronic, more than in an acute, model of epilepsy suggests that they do not merely depend upon seizure severity and/or duration, but may contribute to the epileptic

Acknowledgements

This study was supported by grants from the Italian Ministry for University and Scientific Research (MURST), from the National Council for Research (CNR) and from Telethon.

References (40)

R. Dingledine et al.
Excitatory amino acid receptors in epilepsy
Trends pharmac. Sci.
(1990)
L.F. Donaldson et al.
Inducible receptors
Trends pharmac. Sci.
(1997)
G. Drapeau et al.
Synthesis of bradykinin analogues
Meth. Enzymol.
(1988)
R.S. Fisher
Animal models of the epilepsies
Brain Res. Rev.
(1989)
L.C. Gahring et al.
Interleukin-1α in the brain is induced by audiogenic seizure
Neurobiol. Dis.
(1997)
C. Gall et al.
Seizures, neuropeptide regulation, and mRNA expression in the hippocampus
Prog. Brain Res.
(1990)
C. Geula et al.
Long-term enhancement of K⁺-evoked release of l-glutamate in entorhinal kindled rats
Brain Res.
(1988)
P.M. Headley et al.
Excitatory amino acids and synaptic transmission: the evidence for a physiological function
Trends pharmac. Sci.
(1990)
T. Hokfelt
Neuropetides in perspective: the last ten years
Neuron
(1991)
J.S. Hong et al.
Relationship between hippocampal opioid peptides and seizures
Prog. Neurobiol.
(1993)

N. Kofler et al.

Altered expression of NPY-Y1 receptors in kainic acid-induced epilepsy in rats

Neurosci. Lett.

(1997)

O.H. Lowry et al.

Protein measurement with the Folin phenol reagent

J. biol. Chem.

(1951)

F. Marceau

Kinin B₁ receptors: a review

Immunopharmacology

(1995)

Y. Minamoto et al.

In vivo microdialysis of amino acid neurotransmitters in the hippocampus in amygdaloid kindled rat

Brain Res.

(1992)

A. Muzzolini et al.

Characterization of glutamate and [³H]D-aspartate outflow from various in vitro preparations of the rat hippocampus

Neurochem. Int.

(1997)

J. Perez et al.

Functional effects of d-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Trp-NH₂ and differential changes in somatostatin receptor mRNAs, binding sites and somatostatin release in kainic acid-treated rats

Neuroscience

(1995)

C. Piwko et al.

Status of somatostatin receptor mRNAs and binding sites in rat brain during kindling epileptogenesis

Neuroscience

(1996)

R.J. Racine

Modification of seizure activity by electrical stimulation. II: Motor seizure

Electroenceph. clin. Neurophysiol.

(1972)

D.M. Raidoo et al.

Kinin receptors on human neurones

J. Neuroimmunol.

(1997)

H. Schroder et al.

Specific [³H]L-glutamate binding and [³H]D-aspartate release in the hippocampus of rat after pentylentetrazol kindling and long-term potentiation

Neuroscience

(1994)

Cited by (29)

Bradykinin B<inf>2</inf> receptors increase hippocampal excitability and susceptibility to seizures in mice
2013, Neuroscience
Citation Excerpt :
Altogether, these data integrate previous studies on the involvement of the BK system in epilepsy, and allow putting forward a more comprehensive view. In fact, we have previously suggested that up-regulation of B1 receptors (Ongali et al., 2003) favors hyperexcitability in the kindling model, an effect that could be mediated by an increase in glutamate release (Bregola et al., 1999; Mazzuferi et al., 2005). These findings were confirmed and extended by other groups in other seizure and epilepsy models, like pilocarpine (Argañaraz et al., 2004a,b) and audiogenic kindling (Pereira et al., 2008).
Bradykinin (BK) and its receptors (B1 and B2) may exert a role in the pathophysiology of certain CNS diseases, including epilepsy. In healthy tissues, B2 receptors are constitutively and widely expressed and B1 receptors are absent or expressed at very low levels, but both receptors, particularly B1, are up-regulated under many pathological conditions. Available data support the notion that up-regulation of B1 receptors in brain areas like the amygdala, hippocampus and entorhinal cortex favors the development and maintenance of an epileptic condition. The role of B2 receptors, instead, is still unclear. In this study, we used two different models to investigate the susceptibility to seizures of B1 knockout (KO) and B2 KO mice. We found that B1 KO are more susceptible to seizures compared with wild-type (WT) mice, and that this may depend on B2 receptors, in that (i) B2 receptors are overexpressed in limbic areas of B1 KO mice, including the hippocampus and the piriform cortex; (ii) hippocampal slices prepared from B1 KO mice are more excitable than those prepared from WT controls, and this phenomenon is B2 receptor-dependent, being abolished by B2 antagonists; (iii) kainate seizure severity is attenuated by pretreatment with a non-peptide B2 antagonist in WT and (more effectively) in B1 KO mice. These data highlight the possibility that B2 receptors may have a role in the responsiveness to epileptogenic insults and/or in the early period of epileptogenesis, that is, in the onset of the molecular and cellular events that lead to the transformation of a normal brain into an epileptic one.
Kallikrein 1 is overexpressed by astrocytes in the hippocampus of patients with refractory temporal lobe epilepsy, associated with hippocampal sclerosis
2011, Neurochemistry International
Kallikrein 1 (hK1) is a tissue enzyme responsible for kinin release in inflammatory cascade. This study was delineated to study the distribution and the co-localization of hK1 and kinin B1 and B2 receptors with glial and/or neuronal proteins markers, in the hippocampus of patients with refractory temporal lobe epilepsy, associated with hippocampal sclerosis (TLE-HS), comparing with control tissues. Hippocampal levels of KLK1 mRNA were also measured.
hK1, kinin B1 and B2 receptors, NeuN and GFAP were analyzed using immunohistochemistry and confocal microscopy and KLK1 mRNA was quantified with real time PCR.
Increased expression of hK1 by astrocytes co-localized with GFAP was found, contrasting with kinin B1 and B2 receptors, which were co-localized with NeuN in the sclerotic hippocampus. In addition, KLK1 mRNA was also up-regulated in same tissues.
These data suggest an overexpression of kallikrein–kinin system and a neuron–glia interaction in the inflammatory process present in refractory TLE-HS.
Kinin B1 receptors facilitate the development of temporal lobe epilepsy in mice
2008, International Immunopharmacology
Kinins may play a relevant role in epilepsy. In the present study, we evaluated the hippocampal expression of the remaining kinin receptor in B1 (B1KO) and B2 (B2KO) knockout mice strains during the development of pilocarpine epilepsy model. After pilocarpine injection, animals had their behavior parameters monitored to determine different phases of temporal lobe epilepsy (TLE) progression. Hippocampal mRNA expression was evaluated using specific primers for kinin receptors by Real Time-PCR. B1KO hippocampus from acute, silent and chronic phases showed no differences in B2 receptor mRNA expression when compared to control. An increased B1 receptor mRNA expression in treated B2KO hippocampus (0.97 ± 0.12, acute; 0.86 ± 0.09, silent; and 0.94 ±0.11, chronic phase; p < 0,001) when compared to control (0.12 ± 0.03) was observed. Behavioral and neurochemistry parameters suggest that kinin B1 receptor is fundamental to development of epilepsy on pilocarpine-induced model.
Participation of kallikrein-kinin system in different pathologies
2008, International Immunopharmacology
The general description of kinins refers to these peptides as molecules involved in vascular tone regulation and inflammation. Nevertheless, in the last years a series of evidences has shown that local hormonal systems, such as the kallikrein–kinin system, may be differently regulated and are of pivotal importance to pathophysiological control. The combined interpretations of many recent studies allow us to conclude that the kallikrein–kinin system plays broader and richer roles than those classically described until recently. In this review, we report findings concerning the participation of the kallikrein–kinin system in inflammation, cancer, and in pathologies related to cardiovascular, renal and central nervous systems.
Modulation of B<inf>1</inf> and B<inf>2</inf> kinin receptors expression levels in the hippocampus of rats after audiogenic kindling and with limbic recruitment, a model of temporal lobe epilepsy
2008, International Immunopharmacology
Citation Excerpt :
Studies carried out with B1 knockout mice showed that these animals presented a lesser extent of cellular death, which is associated to the decrease of severity of inflammatory processes in hippocampus and amygdala, as compared to the wild-type animals [25]. In slices from hippocampus of electrically kindled animals, the B1 receptor expression has been associated to an increased release of glutamate [20], which is known to be involved in the development and/or maintenance of brain hyperexcitability. The B2 receptor is also related to some inflammatory phenomena, such as pain and increase of vascular permeability [26].
Epileptic seizures are hypersynchronous, paroxystic and abnormal neuronal discharges. Epilepsies are characterized by diverse mechanisms involving alteration of excitatory and inhibitory neurotransmission that result in hyperexcitability of the central nervous system (CNS). Enhanced neuronal excitability can also be achieved by inflammatory processes, including the participation of cytokines, prostaglandins or kinins, molecules known to be involved in either triggering or in the establishment of inflammation. Multiple inductions of audiogenic seizures in the Wistar audiogenic rat (WAR) strain are a model of temporal lobe epilepsy (TLE), due to the recruitment of limbic areas such as hippocampus and amygdala. In this study we investigated the modulation of the B₁ and B₂ kinin receptors expression levels in neonatal WARs as well as in adult WARs subjected to the TLE model. The expression levels of pro-inflammatory (IL-1β) and anti-inflammatory (IL-10) cytokines were also evaluated, as well as cyclooxygenase (COX-2). Our results showed that the B₁ and B₂ kinin receptors mRNAs were up-regulated about 7- and 4-fold, respectively, in the hippocampus of kindled WARs. On the other hand, the expressions of the IL-1β, IL-10 and COX-2 were not related to the observed increase of expression of kinin receptors. Based on those results we believe that the B₁ and B₂ kinin receptors have a pivotal role in this model of TLE, although their participation is not related to an inflammatory process. We believe that kinin receptors in the CNS may act in seizure mechanisms by participating in a specific kininergic neurochemical pathway.
Acute induction of epileptiform discharges by pilocarpine in the in vitro isolated guinea-pig brain requires enhancement of blood-brain barrier permeability
2008, Neuroscience
Citation Excerpt :
B1 bradykinin receptors mediate excitatory effects in the peripheral nervous system and have little constitutional expression in the CNS (Walker et al., 1995). Bradykinin receptors are upregulated during epileptogenesis (Bregola et al., 1999). Whether this phenomenon has a protective role or represents an epileptogenic event is still debated.
Systemic application of the muscarinic agonist, pilocarpine, is commonly utilized to induce an acute status epilepticus that evolves into a chronic epileptic condition characterized by spontaneous seizures. Recent findings suggest that the status epilepticus induced by pilocarpine may be triggered by changes in the blood–brain barrier (BBB) permeability. We tested the role of the BBB in an acute pilocarpine model by using the in vitro model brain preparation and compared our finding with in vivo data. Arterial perfusion of the in vitro isolated guinea-pig brain with <1 mM pilocarpine did not cause epileptiform activity, but rather reduced synaptic transmission and induced steady fast (20–25 Hz) oscillatory activity in limbic cortices. These effects were reversibly blocked by co-perfusion of the muscarinic antagonist atropine sulfate (5 μM). Brain pilocarpine measurements in vivo and in vitro suggested modest BBB penetration. Pilocarpine induced epileptiform discharges only when perfused with compounds that enhance BBB permeability, such as bradykinin (n=2) or histamine (n=10). This pro-epileptic effect was abolished when the BBB-impermeable muscarinic antagonist atropine methyl bromide (5 μM) was co-perfused with histamine and pilocarpine. In the absence of BBB permeability enhancing drugs, pilocarpine induced epileptiform activity only after arterial perfusion at concentrations >10 mM. Ictal discharges correlated with a high intracerebral pilocarpine concentration measured by high pressure liquid chromatography.
We propose that acute epileptiform discharges induced by pilocarpine treatment in the in vitro isolated brain preparation are mediated by a dose-dependent, atropine-sensitive muscarinic effect promoted by an increase in BBB permeability. Pilocarpine accumulation secondary to BBB permeability changes may contribute to in vivo ictogenesis in the pilocarpine epilepsy model.

View all citing articles on Scopus

View full text

Changes in hippocampal and cortical B1 bradykinin receptor biological activity in two experimental models of epilepsy

Abstract

Section snippets

Preparation of the animals

Results

Discussion

Conclusion

Acknowledgements

Trends pharmac. Sci.

Trends pharmac. Sci.

Meth. Enzymol.

Brain Res. Rev.

Neurobiol. Dis.

Prog. Brain Res.

Brain Res.

Trends pharmac. Sci.

Neuron

Prog. Neurobiol.

Neurosci. Lett.

J. biol. Chem.

Immunopharmacology

Brain Res.

Neurochem. Int.

Neuroscience

Neuroscience

Electroenceph. clin. Neurophysiol.

J. Neuroimmunol.

Neuroscience

Changes in hippocampal and cortical B₁ bradykinin receptor biological activity in two experimental models of epilepsy