Kinin B2 receptor can play a neuroprotective role in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by cognitive decline, presence of amyloid-beta peptide (Aß) aggregates and neurofibrillary tangles. Kinins act through B1 and B2 G-protein coupled receptors (B1R and B2R). Chronic infusion of Aß peptide leads to memory impairment and increases in densities of both kinin receptors in memory processing areas. Similar memory impairment was observed in C57BL/6 mice (WTAß) but occurred earlier in mice lacking B2R (KOB2Aß) and was absent in mice lacking B1R (KOB1Aß). Thus, the aim of this study was to evaluate the participation of B1R and B2R in Aß peptide induced cognitive deficits through the evaluation of densitiesof kinin receptors, synapses, cell bodies and number of Aß deposits in brain ofWTAß, KOB1Aß and KOB2Aß mice. An increase in B2R density was observed in both WTAß and KOB1Aß in memory processing related areas. KOB1Aß showed a decrease in neuronal density and an increase in synaptic density and, in addition, an increase in Aß deposits in KOB2Aß was observed. In conclusion, memory preservation in KOB1Aß, could be due to the increase in densities of B2R, suggesting a neuroprotective role for B2R, reinforced by the increased number of Aß plaques in KOB2Aß. Our data point to B2R as a potential therapeutic target in AD.

Kallikrein-kinin system mediated inflammation in Alzheimer's disease in vivo.

The Kallikrein-Kinin System (KKS) has been associated to inflammatory and immunogenic responses in the peripheral and central nervous system by the activation of two receptors, namely B1 receptor and B2 receptor. The B1 receptor is absent or under-expressed in physiological conditions, being up-regulated during tissue injury or in the presence of cytokines. The B2 receptor is constitutive and mediates most of the biological effects of kinins. Some authors suggest a link between the KKS and the neuroinflammation in Alzheimer's disease (AD). We have recently described an increase in bradykinin (BK) in the cerebrospinal fluid and in densities of B1 and B2 receptors in brain areas related to memory, after chronic infusion of amyloid-beta (Aß) peptide in rats, which was accompanied by memory disruption and neuronal loss. Mice lacking B1 or B2 receptors presented reduced cognitive deficits related to the learning process, after acute intracerebroventricular (i.c.v). administration of Aß. Nevertheless, our group showed an early disruption of cognitive function by i.c.v. chronic infusion of Aß after a learned task, in the knock-out B2 mice. This suggests a neuroprotective role for B2 receptors. In knock-out B1 mice the memory disruption was absent, implying the participation of this receptor in neurodegenerative processes. The acute or chronic infusion of Aß can lead to different responses of the brain tissue. In this way, the proper involvement of KKS on neuroinflammation in AD probably depends on the amount of Aß injected. Though, BK applied to neurons can exert inflammatory effects, whereas in glial cells, BK can have a potential protective role for neurons, by inhibiting proinflammatory cytokines. This review discusses this duality concerning the KKS and neuroinflammation in AD in vivo.

Pressor effect mediated by bradykinin in the paratrigeminal nucleus of the rat.

1. The participation of the paratrigeminal nucleus (Pa5) in the pressor response produced by bradykinin in the dorsolateral medulla of rats was investigated. The microinjection of 6 pmol of bradykinin directly over the paratrigeminal nucleus of unanaesthetized rats produced a significant increase in arterial pressure and a moderate increase in heart rate. 2. Bradykinin microinjections in different sites surrounding the Pa5 compromising the external cuneate nucleus, the trigeminal nucleus, the lateral and ventral spinal trigeminal tract and the dorsal trigeminal tract rostral and caudal to the Pa5 did not elicit significant pressor responses. In contrast, microinjections in the paratrigeminal nucleus produced pressor effects. Injections in the dorsolateral medulla directly over the paratrigeminal nucleus produced larger responses than when injections were made in the nucleus. Saline injections in the different nuclei did not produce pressor effects. 3. Neurochemical lesioning of the Pa5, with microinjections of ibotenic acid in the Pa5, abolished the pressor response to bradykinin injected over the lesioned nucleus. The effect was present, however, when bradykinin was injected on the contralateral side to the lesion, over the intact nucleus of the same animal. Pretreatment with capsaicin (injected in the lateral cerebral ventricle), which causes selective degeneration of afferent sensory fibres, did not alter the pressor effect of bradykinin injected over the paratrigeminal nucleus. 4. Dose-related responses were produced by different concentrations of bradykinin (0.6-1.8 pmol) microinjected over the nucleus. The bradykinin receptor antagonist HOE 140, injected over the paratrigeminal nucleus 30 min earlier, abolished the pressor response caused by bradykinin. 5. Low doses of bradykinin injected in or directly over the paratrigeminal nucleus increased arterial pressure and caused a small increase in heart rate by stimulating kinin receptors of the paratrigeminal nucleus in the dorsolateral medulla of awake and unrestrained rats. The pattern of the response was consistent with that of sympathetic stimulation. The paratrigeminal nucleus, which receives primary afferents and projects to the nucleus tractus solitarii and the rostral ventral lateral medulla, may be positioned as relay nucleus possibly connecting sensory input to structures that regulate blood pressure.