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 B1 receptor antagonists as antiepileptic agents, and for B2 receptor antagonists (and/or B1 agonists) in the treatment of stroke. Functional B1 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

Induction of B1 bradykinin receptors in the kindled brain.

The data suggest that the B1 BK receptors may play a role in the physiopathology of epilepsy, and may represent a new interesting therapeutic target. Tools are available to challenge this idea both pharmacologically (using B1 and B2 receptor antagonists) and genetically (using B1 and B2 receptor knock-outs)

Increases of spinal kinin receptor binding sites in two rat models of insulin resistance

An autoradiographic study was conducted to determine whether kinin receptors are altered in the rat spinal cord in two experimental models of chronic hyperglycemia and insulin resistance. Sprague-Dawley rats were given 10% d-glucose in their drinking water alone or with insulin (9 mU/kg/min with osmotic pumps) for 4 weeks. Both groups and control rats were treated either with a normal chow diet or with an alpha-lipoic acid-supplemented diet as antioxidant therapy. After 4 weeks of treatment, glycemia, insulinemia, blood pressure, insulin resistance index, the production of superoxide anion in the aorta and the density of B1 receptor binding sites in the dorsal horn were significantly increased in the two models. These effects were prevented or attenuated by alpha-lipoic acid. In contrast, B2 receptor binding sites of most spinal cord laminae were increased in the glucose group only and were not affected by alpha-lipoic acid. Results show that chronic hyperglycemia associated with insulin resistance increases B1 and B2 receptor binding sites in the rat spinal cord through distinct mechanisms, including the oxidative stress for the B1 receptor

Expression of kinin B-1 receptors in the spinal cord of streptozotocin-diabetic rat

Previous studies have reported cardiovascular and nociceptive responses after intrathecal injection of kinin B1 receptor (B1R) agonists in the model of streptozotocin (STZ)-diabetic rat (diabetic). The aim of this study was to measure the early up-regulation of B1R binding sites andmRNA in the thoracic spinal cord of diabetic and control rats. Data show signi¢cant increases of speci¢c B1R binding sites in the dorsal horn of diabetic rats 2 days (+315%), 7 days (+303%) and 21days (+181%) after STZ treatment. Levels of mRNAwere signi¢cantly increased (+68%) at 2 and 7 days but not at 21days.These data bring the ¢rstmolecular evidence for an early up-regulation of B1R in the spinal cord of diabetic rat. NeuroReport 15:2463^2466 c 2004 LippincottWilliams &Wilkins

Autoradiographic analysis of rat brain kinin B-1 and B-2 receptors: Normal distribution and alterations induced by epilepsy

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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 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 B1KO 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