Bradykinin B2 receptors increase hippocampal excitability and susceptibility to seizures in mice.

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.

Role of kinin B1 and B2 receptors in a rat model of neuropathic pain.

Kinin B1 and B2 receptor (R) gene expression (mRNA) is increased in the sensory system after peripheral nerve injury. This study measured the densities of B1R and B2R binding sites in the spinal cord and dorsal root ganglia (DRG) by quantitative autoradiography, and evaluated the effects of two selective non-peptide antagonists at B1R (LF22-0542) and B2R (LF16-0687) on pain behavior after partial ligation of the left sciatic nerve. Increases of B1R binding sites were seen in superficial laminae of the ipsi- and contralateral spinal cord at 2 and 14 days while B2R binding sites were increased on the ipsilateral side at 2 days and on both sides at 14 days. In DRG, B1R and B2R binding sites were significantly increased at 2 days (ipsilateral) and 14 days on both sides. Whereas tactile allodynia started to develop progressively from 2 to 25 days post-ligation, the occurrence of cold allodynia and thermal hyperalgesia became significant from day 8 and day 14 post-ligation, respectively. At day 21 after sciatic nerve ligation, thermal hyperalgesia was blocked by LF22-0542 (10 mg/kg, s.c.) and LF16-0687 (3 mg/kg, s.c.), yet both antagonists had no effect on tactile and cold allodynia. Data highlight the implication of both kinin receptors in thermal hyperalgesia but not in tactile and cold allodynia associated with peripheral nerve injury. Hence LF22-0542 and LF16-0687 present therapeutic potential for the treatment of some aspects of neuropathic pain.

Oxidative stress and cerebrovascular dysfunction in mouse models of Alzheimer's disease.

Several factors have been implicated in Alzheimer's disease (AD) but there is no definite conclusion as to the main pathogenic agents. Mutations in the amyloid precursor protein (APP) that lead to increased production of amyloid beta peptide (A beta) are associated with the early-onset, familial forms of AD. However, in addition to ageing, the most common risk factors for the sporadic, prevalent form of AD are hypertension, hypercholesterolaemia, ischaemic stroke, the ApoE4 allele and diabetes, all characterized by a vascular pathology. In AD, the vascular pathology includes accumulation of A beta in the vessel wall, vascular fibrosis, and other ultrastructural changes in constituent endothelial and smooth muscle cells. Moreover, the ensuing chronic cerebral hypoperfusion has been proposed as a determinant factor in the accompanying cognitive deficits. In transgenic mice that overexpress mutated forms of the human APP (APP mice), the increased production of A beta results in vascular oxidative stress and loss of vasodilatory function. The culprit molecule, superoxide, triggers the synthesis of other reactive oxygen species and the sequestration of nitric oxide (NO), thus impairing resting cerebrovascular tone and NO-dependent dilatations. The A beta-induced cerebrovascular dysfunction can be completely abrogated in aged APP mice with antioxidant therapy. In contrast, in mice that overproduce an active form of the cytokine transforming growth factor-beta1 and recapitulate the vascular structural changes seen in AD, antioxidants have no beneficial effect on the accompanying cerebrovascular deficits. This review discusses the beneficial role and limitations of antioxidant therapy in AD cerebrovascular pathology.

Involvement of kinin B1 receptor and oxidative stress in sensory abnormalities and arterial hypertension in an experimental rat model of insulin resistance.

Diabetes Mellitus leads to pain neuropathy and cardiovascular complications which remain resistant to current therapies involving the control of glycaemia. This study aims at defining the contribution of kinin B(1) receptor (B(1)R) and the oxidative stress on sensory abnormalities and arterial hypertension in a rat model of insulin resistance. Rats were fed with 10% d-glucose for a chronic period of 12-14 weeks and the impact of a diet supplemented with alpha-lipoic acid, a potent antioxidant, was determined on tactile and cold allodynia, arterial hypertension and the expression of kinin B(1)R (real-time PCR and autoradiography) in several tissues. Acute effects of brain penetrant (LF22-0542) and peripherally acting (R-715) B(1)R antagonists were also assessed. Glucose-fed rats exhibited tactile and cold allodynia along with increases in systolic blood pressure between 4 and 12 weeks; these alterations were alleviated by alpha-lipoic acid. The latter regimen also decreased significantly increased plasma levels of insulin and glucose and insulin resistance (HOMA index) at 14 weeks. B(1)R mRNA was virtually absent in liver, aorta, lung, kidney and spinal cord isolated from control rats, yet B(1)R mRNA was markedly increased in all tissues in glucose-fed rats. Up-regulated B(1)R mRNA and B(1)R binding sites (spinal cord) were significantly reduced by alpha-lipoic acid in glucose-fed rats. LF22-0542 reduced tactile and cold allodynia (3h) and reversed arterial hypertension (3-48h) in glucose-fed rats. R-715 abolished tactile and cold allodynia but had not effect on blood pressure. Data suggest that the oxidative stress contributes to the induction and up-regulation of B(1)R in the model of insulin resistance induced by glucose feeding. The over expressed B(1)R contributes centrally to arterial hypertension and in the periphery to sensory abnormalities.

Targeting kinin receptors for the treatment of neurological diseases.

Kinins (bradykinin, kallidin and their active metabolites) are peptide autacoids with established functions in cardiovascular homeostasis, contraction and relaxation of smooth muscles, inflammation and nociception. They are believed to play a role in disease states like asthma, allergies, rheumatoid arthritis, cancer, diabetes, endotoxic and pancreatic shock, and to contribute to the therapeutic effects of ACE inhibitors in cardiovascular diseases. Although kinins are also neuromediators in the central nervous system, their involvement in neurological diseases has not been intensively investigated thus far. This review analyzes the potential of central kinin receptors as therapeutic targets for neurological disorders. Initial data highlight potential roles for B(1) receptor antagonists as antiepileptic agents, and for B(2) receptor antagonists (and/or B(1) agonists) in the treatment of stroke. Functional B(1) receptors located on T-lymphocytes and on the blood brain-barrier are also putative targets for the management of multiple sclerosis. However, successful elucidation of the therapeutic value of these new pharmacological approaches will require refinement of our knowledge on the physiology and cellular localization of central kinin receptors.

Dopamine D(1) and D(2) receptors in the forebrain of dystonia musculorum mutant mice: an autoradiographic survey in relation to dopamine contents.

Dystonia musculorum (dt(J)/dt(J)) mutant mice suffer from a degeneration of spinocerebellar tracts as well as a dystrophy of peripheral sensory tracts. This neurological mutant has been proposed as an animal model of human cerebellar ataxia, in particular of the Friedreich's type; thus, it was deemed of interest to examine the endogenous contents of dopamine (DA) and metabolites as well as the distribution of DA receptors of the D(1) and D(2) subtypes, in order to delimit the biochemical characteristics of this pathological disorder, and determine an eventual dopaminergic dysfunction in this mutant. Tissue DA and its major metabolites 3, 4-dihydroxyphenylacetic acid, homovanillic acid and 3-methoxytyramine were measured by HPLC coupled to electrochemical detection in six cortical regions, in four divisions of rostral neostriatum and two halves of caudal neostriatum, as well as in olfactory bulb, nucleus accumbens, septum, amygdala, hippocampus, thalamus, hypothalamus, brainstem, cerebellum, substantia nigra, and ventral tegmental area. The only significant difference between dt(J)/dt(J) mice and wild-type controls was an increase in hypothalamic DA contents (+47%). Quantitative autoradiography with [(3)H]SCH23390 and [(3)H]raclopride, to label D(1) and D(2) receptors, respectively, revealed only moderate changes in receptor densities in a few localized regions. In dt(J)/dt(J) mutants, D(1) receptor numbers were found to be higher in thalamus (+27%) as well as in the medio-dorsal (+16%) and in the latero-dorsal (+16%) quadrants of rostral neostriatum, while D(2) receptor densities were greater in the medio-ventral (+32%) and the latero-dorsal (+17%) quadrants. The present results indicate an overall conservation of dopaminergic functions, albeit the few localized sites of increased D(1) and D(2) receptor densities, and that are seemingly independent of the DA innervation pattern, as revealed by the tissue measurements of DA and metabolites. They also rule out a major pathology linked to deficits in DA neurotransmission, and validate this mutant as an animal model of human cerebellar ataxia, probably of the Friedreich type.