Current antidepressant therapies meet with variable therapeutic success and there is increasing interest in therapeutic approaches not based on monoamine signaling. Histone deacetylase 6 (HDAC6), which also deacetylates α-tubulin shows altered expression in mood disorders and HDAC6 knockout mice mimic traditional antidepressant treatments. Nonetheless, a mechanistic understanding for HDAC6 inhibitors in the treatment of depression remains elusive. Previously, we have shown that sustained treatment of rats or glioma cells with several antidepressants translocates Gα from lipid rafts toward increased association with adenylyl cyclase (AC). Concomitant with this is a sustained increase in cAMP production. While Gα modifies microtubule dynamics, tubulin also acts as an anchor for Gα in lipid-rafts. Since HDAC-6 inhibitors potentiate α-tubulin acetylation, we hypothesize that acetylation of α-tubulin disrupts tubulin-Gα raft-anchoring, rendering Gα free to activate AC. To test this, C6 Glioma (C6) cells were treated with the HDAC-6 inhibitor, tubastatin-A. Chronic treatment with tubastatin-A not only increased α-tubulin acetylation but also translocated Gα from lipid-rafts, without changing total Gα. Reciprocally, depletion of α-tubulin acetyl-transferase-1 ablated this phenomenon. While escitalopram and imipramine also disrupt Gα/tubulin complexes and translocate Gα from rafts, they evoke no change in tubulin acetylation. Finally, two indicators of downstream cAMP signaling, cAMP response element binding protein phosphorylation (pCREB) and expression of brain-derived-neurotrophic-factor (BDNF) were both elevated by tubastatin-A. These findings suggest HDAC6 inhibitors show a cellular profile resembling traditional antidepressants, but have a distinct mode of action. They also reinforce the validity of antidepressant-induced Gα translocation from lipid-rafts as a biosignature for antidepressant response that may be useful in the development of new antidepressant compounds.
Rationale Cannabinoid CB1 receptor agonists vary in efficacy in vitro; however, relationships between efficacy and behavioral effects are unclear. Objective This study examined the relationship between apparent CB1 agonist efficacy and in vivo effects. Methods Male C57BL/6J mice responded for food under a fixed ratio 30 schedule; rectal temperature was measured. Sensitivity of the mice to cannabinoid agonists (rank order efficacy in vitro reported to be CP 55940>anandamide>Δ9-tetrahydrocannabinol; Δ9-THC) and a non-cannabinoid (the benzodiazepine midazolam) was determined before, during, and after discontinuation of daily Δ9-THC treatment (32 mg/kg/day, i.p.). Rimonabant was combined with cannabinoids to examine whether CB1 receptors mediated effects on response rate. Results Δ9-THC, CP 55940, anandamide, and midazolam decreased responding at doses smaller than those producing hypothermia. Rimonabant antagonized the rate-decreasing effects of Δ9-THC and CP 55940, but not those of anandamide. Δ9-THC treatment produced tolerance for both rate-decreasing and hypothermic effects. Δ9-THC treatment did not change sensitivity to the rate-decreasing effects of CP 55940, but produced cross-tolerance to CP 55940 for hypothermic effects. Δ9-THC treatment did not modify sensitivity to anandamide and midazolam. Conclusions CB1 receptors mediate the operant rate-decreasing effects of Δ9-THC and CP 55940, but not anandamide, in mice. CB1 agonist efficacy is an important determinant of in vivo effects, especially with regard to the magnitude of tolerance and cross-tolerance resulting from daily Δ9-THC treatment. This applies not only to different cannabinoids when measuring the same effect but also to the same cannabinoid when measuring different effects.
BACKGROUND Vascular endothelial growth factor-B (VEGF-B) activates cytoprotective/antiapoptotic and minimally angiogenic mechanisms via VEGF receptors. Therefore, VEGF-B might prove an ideal candidate for the treatment of dilated cardiomyopathy, which displays modest microvascular rarefaction and increased rate of apoptosis. OBJECTIVES We evaluated VEGF-B gene therapy in a canine model of tachypacing-induced dilated cardiomyopathy. METHODS Chronically instrumented dogs underwent cardiac tachypacing for 28 days. Adeno-associated-9 viral vectors carrying VEGF-B167 genes were infused intracoronarily at the beginning of the pacing protocol or during compensated heart failure (HF). Moreover, we tested a novel VEGF-B167 transgene controlled by the atrial natriuretic factor (ANF) promoter. RESULTS Compared to controls, VEGF-B167 markedly preserved diastolic and contractile function and attenuated ventricular chamber remodeling, halting the progression from compensated to decompensated HF. ANF-VEGF-B167 expression was low in normo-functioning hearts and stimulated by cardiac pacing; thus, it functioned as an ideal therapeutic transgene, active only under pathological conditions. CONCLUSIONS Our results, obtained with a standard technique of interventional cardiology in a clinically relevant animal model, support VEGF-B167 gene transfer as an affordable and highly effective new therapy for nonischemic HF.
These data are consistent with previous positron emission tomography findings of MP-mediated reduction in lateral prefrontal activity accompanied by improved cognitive performance.
BACKGROUND: Rates of atherosclerotic cardiovascular disease (ASCVD) are strikingly high in India compared to Western countries and are increasing. Moreover, ASCVD events occur at a younger age with only modest hypercholesterolemia, most commonly with low levels of high-density lipoprotein cholesterol. The course of ASCVD also appears to be more fulminant with higher mortality.OBJECTIVE: In light of these issues, the Lipid Association of India (LAI) endeavored to develop revised guidelines with more aggressive low-density lipoprotein cholesterol (LDL-C) goals in secondary prevention and for patients with familial hypercholesterolemia compared to guidelines in the United States and other countries.METHODS: Owing to the paucity of clinical outcomes data in India, it was necessary to place major emphasis on expert opinion as a complement to randomized placebo-controlled data generated mostly in non-Indian cohorts. To facilitate this process, the LAI conducted a series of 19 meetings among 162 lipid specialists in 13 cities throughout India over a period of 11 months before formulating this expert consensus statement.RESULTS: The LAI recommends an LDL-C goal ,50 mg/dL in all patients in secondary prevention or very high-risk primary prevention but proposes an optional goal #30 mg/dL in category A extreme-risk patients (eg, coronary artery disease 1 familial hypercholesterolemia) and a recommended goal #30 mg/dL in category B extreme-risk patients [coronary artery disease 1 (1) diabetes and polyvascular disease/$3 major ASCVD risk factors/end organ damage, or (2) recurrent acute coronary syndrome within 12 months despite LDL-C ,50 mg/dL, or (3) homozygous familial hypercholesterolemia].CONCLUSIONS: More aggressive LDL-C goals are needed for prevention of ASCVD in India, as described in this expert consensus statement. Use of statins and ezetimibe needs to increase in India in combination with improved control of other ASCVD risk factors. Proprotein convertase subtilisin kexin type 9 inhibitors can improve LDL-C goal achievement in patients with refractory hypercholesterolemia.
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