The role of PKC/ERK1/2 signaling in the anti-inflammatory effect of tetracyclic triterpene euphol on TPA-induced skin inflammation in mice

AbstractInflammation underlies the development and progression of a number of skin disorders including psoriasis, atopic dermatitis and cancer. Therefore, novel antiinflammatory agents are of great clinical interest for prevention and treatment of these conditions. Herein, we demonstrated the underlying molecular mechanisms of the antiinflammatory activity of euphol, a tetracyclic triterpene isolated from the sap of Euphorbia tirucalli, in skin inflammation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in mice. Topical application of euphol (100μg/ear) significantly inhibited TPA-induced ear edema and leukocyte influx through the reduction of keratinocyte-derived chemokine (CXCL1/KC) and macrophage inflammatory protein (MIP)-2 levels. At the intracellular level, euphol reduced TPA-induced extracellular signal-regulated protein kinase (ERK) activation and cyclooxygenase-2 (COX-2) upregulation. These effects were associated with euphol's ability to prevent TPA-induced protein kinase C (PKC) activation, namely PKCα and PKCδ isozymes. Our data indicate that topical application of euphol markedly inhibits the inflammatory response induced by TPA. Thus, euphol represents a promising agent for the management of skin diseases with an inflammatory component

Experimental hypertension increases spontaneous intracerebral hemorrhages in a mouse model of cerebral amyloidosis

Hypertension and cerebral amyloid angiopathy (CAA) are major risk factors for intracerebral hemorrhage (ICH); however the mechanisms of interplay between the two are not fully understood. We investigated the effect of hypertension in a transgenic mouse model with Alzheimer’s-like pathology (Tg2576) treating them with angiontensin II and L-N(G)-nitroarginine methyl ester. A similar increase in systolic blood pressure was observed in both Tg2576 and control mice; however Tg2576 mice developed signs of stroke with a markedly shorter latency. Cerebral deposition of amyloid beta promotes the hypertension-induced ICH, thus supporting the notion that hypertension is a risk factor for ICH among patients with CAA

Experimental hypertension increases spontaneous intracerebral hemorrhages in a mouse model of cerebral amyloidosis.

Hypertension and cerebral amyloid angiopathy (CAA) are major risk factors for intracerebral hemorrhage (ICH); however the mechanisms of interplay between the two are not fully understood. We investigated the effect of hypertension in a transgenic mouse model with Alzheimer's-like pathology (Tg2576) treating them with angiotensin II and L-N(G)-nitroarginine methyl ester. A similar increase in systolic blood pressure was observed in both Tg2576 and control mice; however Tg2576 mice developed signs of stroke with a markedly shorter latency. Cerebral deposition of amyloid beta promotes the hypertension-induced ICH, thus supporting the notion that hypertension is a risk factor for ICH among patients with CAA

Neuropathic pain-like behavior after brachial plexus avulsion in mice: the relevance of kinin B-1 and B-2 receptors

The relevance of kinin B-1 (B1R) and B-2 (B2R) receptors in the brachial plexus avulsion (BPA) model was evaluated in mice, by means of genetic and pharmacological tools. BPA-induced hypernociception was absent in B1R, but not in B2R, knock-out mice. Local or intraperitoneal administration of the B2R antagonist Hoe 140 failed to affect BPA-induced mechanical hypernociception. Interestingly, local or intraperitoneal treatment with B1R antagonists, R-715 or SSR240612, dosed at the time of surgery, significantly reduced BPA-evoked mechanical hypernociception. Intrathecal or intracerebroventricular administration of these antagonists, at the surgery moment, did not prevent the hypernociception. Both antagonists, dosed by intraperitoneal or intrathecal routes (but not intracerebroventricularly) 4 d after the surgery, significantly inhibited the mechanical hypernociception. At 30 d after the BPA, only the intracerebroventricular treatment effectively reduced the hypernociception. A marked increase in B1R mRNA was observed in the hypothalamus, hippocampus, thalamus, and cortex at 4 d after BPA and only in the hypothalamus and cortex at 30 d. in the spinal cord, a slight increase in B1R mRNA expression was observed as early as at 2 d. Finally, an enhancement of B1R protein expression was found in all the analyzed brain structures at 4 and 30d after the BPA, whereas in the spinal cord, this parameter was augmented only at 4d. the data providenewevidence on the role of peripheral and central kinin B1R in the BPA model of neuropathic pain. Selective B1R antagonists might well represent valuable tools for the management of neuropathic pain.Univ Fed Santa Catarina, Dept Pharmacol, Ctr Biol Sci, BR-88049900 Florianopolis, SC, BrazilPontificia Univ Catolica Rio Grande do Sul, Sch Dent, BR-90169900 Porto Alegre, RS, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Biophys, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Biophys, BR-04023900 São Paulo, BrazilWeb of Scienc

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

Previous studies have demonstrated that targeting bradykinin receptors is a promising strategy to counteract the cognitive impairment related with aging and Alzheimer's disease (AD). The hippocampus is critical for cognition, and abnormalities in this brain region are linked to the decline in mental ability. Nevertheless, the impact of bradykinin signaling on hippocampal function is unknown. Therefore, we sought to determine the role of hippocampal bradykinin receptors BR and BR on the cognitive decline of middle-aged rats. Twelve-month-old rats exhibited impaired ability to acquire and retrieve spatial information in the Morris water maze task. A single intra-hippocampal injection of the selective BR antagonist des-Arg-[Leu]-bradykinin (DALBK, 3 nmol), but not the selective BR antagonist D-Arg-[Hyp,Thi,D-Tic,Oic]-BK (Hoe 140, 3 nmol), reversed the spatial learning and memory deficits on these animals. However, both drugs did not affect the cognitive function in 3-month-old rats, suggesting absence of nootropic properties. Molecular biology analysis revealed an up-regulation of B1R expression in the hippocampal CA1 sub-region and in the pre-frontal cortex of 12-month-old rats, whereas no changes in the BR expression were observed in middle-aged rats. These findings provide new evidence that inappropriate hippocampal BR expression and activation exert a critical role on the spatial learning and memory deficits in middle-aged rats. Therefore, selective BR antagonists, especially orally active non-peptide antagonists, may represent drugs of potential interest to counteract the age-related cognitive decline