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Oxidative stress plays an important role in the pathophysiology of several vascular diseases such as atherosclerosis, and great attention has been placed on the protective role of heme oxygenase-1 (HO-1) for vasculature against oxidant-induced injury. We tested whether the protective effects of YS 51, 1-(beta-naphtyl-methyl)-6,7-dihydroxy-1,2,3,4,-tetrahydroisoquinoline, against hydrogen peroxide (H2O2)-induced cell injury is associated with HO-1 activity in bovine aortic endothelial cells (BAEC). YS 51 increased HO-1 expression and activity in concentration-dependent manners (10-100 microM) and time-dependent manners (1, 3, 6, 18 h), which were correlated well with its protective effect against H2O2-induced injury. Zinc protoporphyrin IX (ZnPP IX), a HO inhibitor, significantly inhibited the effect of YS 51 (50 microM). In contrast, [Ru(CO)3(Cl)2]2 (CORM-2, a CO releasing molecule) but not bilirubin protected against H2O2-induced injury. Oxyhemoglobin (HbO2) used as a CO scavenger significantly inhibited the protective effect of both YS 51 and CORM-2. Furthermore, both YS 51 and CORM-2 significantly reduced H2O2-induced intracellular reactive oxygen species (ROS) production; however, this was counteracted by ZnPP IX, HbO2 and deferoxamine. We found evidence for the involvement of PI3/Akt kinase and ERK1/2 pathways in HO-1 induction by YS-51. Taken together, we conclude that CO is, at least, responsible for the YS 51-mediated protective action of endothelial cells against oxidant stress via HO-1 gene induction, involving the activation of the PI3/Akt and ERK1/2 kinase pathways. Thus, YS 51 may be useful in oxidative stress-induced vascular disorders.

It has been proposed that the inducible isoform of heme oxygenase (HO) protects cells against oxidant-mediated injury. Although components of Agastache rugosa showed antioxidant effect, it is unclear this effect is related with HO-1 activity. Thus, we investigated the effects of Agastache rugosa leaf extract (ALE) on HO-1 protein expression and enzyme activity, and its protective effect against H(2)O(2)-induced oxidative damage was also investigated using RAW264.7 macrophage cells. Results showed that ALE concentration dependently increased HO-1 protein and enzyme activity, and protected cells from H(2)O(2)-induced cytotoxicity, with an IC(50) of 0.526 mg/ml. Hemin, a HO-1 inducer, also showed similar effect to ALE. Furthermore, the protective effect of both ALE and hemin was inhibited by a HO inhibitor, zinc protoporphyrin IX. The expression of HO-1 protein by ALE was reduced by pretreatment with LY83583 and ODQ, specific inhibitors of guanylate cyclase, but not by PKA inhibitors, H89 and KT5720, indicating that PKG signaling pathway regulates HO-1 induction by ALE. Taken together, it is concluded that PKG-dependent HO-1 induction is one of the important antioxidant mechanisms by which ALE protects RAW264.7 cells from H(2)O(2). Thus, ALE along with other actions may be beneficial for the treatment of oxidant-induced cellular injuries.

We hypothesized that catecholamines through beta-adrenoceptor might modulate macrophage function. We showed that isoproterenol concentration-dependently induced HO-1 production through beta(1)-but not beta(2)-adrenoceptor. Production was increased by forskolin and inhibited by pretreatment with the PKA inhibitor, H-89. Furthermore, induction of HO-1 by isoproterenol effectively protected RAW264.7 cells from effects of glucose oxidase treatment, which was abrogated either by HO-1 inhibitor, ZnPP IX and beta-adenoceptor antagonist, propranolol. Thus, stimulation of HO-1 production through beta(1)-adenoceptors, and via the PKA pathways by isoproterenol, can enable RAW264.7 cells to resist oxidant stress, suggesting that catecholamine hormones may be necessary, at least, to maximize defending role of macrophages.

Epilepsy, marked by abnormal and excessive brain neuronal activity, is linked to the activation of L-type voltage-gated calcium channels (LTCCs) in neuronal membranes. LTCCs facilitate the entry of calcium (Ca2+) and other metal ions, such as zinc (Zn2+) and magnesium (Mg2+), into the cytosol. This Ca2+ influx at the presynaptic terminal triggers the release of Zn2+ and glutamate to the postsynaptic terminal. Zn2+ is then transported to the postsynaptic neuron via LTCCs. The resulting Zn2+ accumulation in neurons significantly increases the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, contributing to reactive oxygen species (ROS) generation and neuronal death. Amlodipine (AML), typically used for hypertension and coronary artery disease, works by inhibiting LTCCs. We explored whether AML could mitigate Zn2+ translocation and accumulation in neurons, potentially offering protection against seizure-induced hippocampal neuronal death. We tested this by establishing a rat epilepsy model with pilocarpine and administering AML (10 mg/kg, orally, daily for 7 days) post-epilepsy onset. We assessed cognitive function through behavioral tests and conducted histological analyses for Zn2+ accumulation, oxidative stress, and neuronal death. Our findings show that AML's LTCC inhibition decreased excessive Zn2+ accumulation, reactive oxygen species (ROS) production, and hippocampal neuronal death following seizures. These results suggest amlodipine's potential as a therapeutic agent in seizure management and mitigating seizures' detrimental effects. [ABSTRACT FROM AUTHOR]

Glutathione (GSH) is necessary for maintaining physiological antioxidant function, which is responsible for maintaining free radicals derived from reactive oxygen species at low levels and is associated with improved cognitive performance after brain injury. GSH is produced by the linkage of tripeptides that consist of glutamic acid, cysteine, and glycine. The adequate supplementation of GSH has neuroprotective effects in several brain injuries such as cerebral ischemia, hypoglycemia, and traumatic brain injury. Brain injuries produce an excess of reactive oxygen species through complex biochemical cascades, which exacerbates primary neuronal damage. GSH concentrations are known to be closely correlated with the activities of certain genes such as excitatory amino acid carrier 1 (EAAC1), glutamate transporter-associated protein 3–18 (Gtrap3-18), and zinc transporter 3 (ZnT3). Following brain-injury-induced oxidative stress, EAAC1 function is negatively impacted, which then reduces cysteine absorption and impairs neuronal GSH synthesis. In these circumstances, vesicular zinc is also released into the synaptic cleft and then translocated into postsynaptic neurons. The excessive influx of zinc inhibits glutathione reductase, which inhibits GSH's antioxidant functions in neurons, resulting in neuronal damage and ultimately in the impairment of cognitive function. Therefore, in this review, we explore the overall relationship between zinc and GSH in terms of oxidative stress and neuronal cell death. Furthermore, we seek to understand how the modulation of zinc can rescue brain-insult-induced neuronal death after ischemia, hypoglycemia, and traumatic brain injury. [ABSTRACT FROM AUTHOR]

Abstract: We hypothesized that catecholamines through β-adrenoceptor might modulate macrophage function. We showed that isoproterenol concentration-dependently induced HO-1 production through β1-but not β2-adrenoceptor. Production was increased by forskolin and inhibited by pretreatment with the PKA inhibitor, H-89. Furthermore, induction of HO-1 by isoproterenol effectively protected RAW264.7 cells from effects of glucose oxidase treatment, which was abrogated either by HO-1 inhibitor, ZnPP IX and β-adenoceptor antagonist, propranolol. Thus, stimulation of HO-1 production through β1-adenoceptors, and via the PKA pathways by isoproterenol, can enable RAW264.7 cells to resist oxidant stress, suggesting that catecholamine hormones may be necessary, at least, to maximize defending role of macrophages. [Copyright &y& Elsevier]