Pharmacological research : the official journal of the Italian Pharmacological Society
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Most of cases of Parkinson's disease (PD) have a sporadic origin, with their causes mostly unknown, although overexposure to some environmental factors has been found to occur in some cases. Other forms of parkinsonism are the consequence of dominant or recessive mutations in specific genes, e.g. α-synuclein, parkin and, more recently, leucine-rich repeat kinase 2 (LRRK2), whose G2019S mutation represents the most prevalent form of late-onset, autosomal dominant familial PD. A transgenic mouse model expressing the G2019S mutation of LRRK2 is already available and apparently may represent a valuable experimental model for investigating PD pathogenesis and novel treatments. ⋯ Furthermore, there were no changes in the status of the CB2 receptor, as well as in other elements of the endocannabinoid signaling, in the basal ganglia, but, paradoxically, the selective activation of this receptor partially reversed the deficits in the hanging-wire test of LRRK2 transgenic mice. This was accompanied by normalization in LAMP-1 immunolabelling in the basal ganglia, although it is possible that other CNS structures, remaining to be identified, are involved in the behavioral improvement. In summary, our data support the interest of the CB2 receptor as a potential pharmacological target in LRRK2 transgenic mice, although the neuronal substrates underlying these benefits might be not completely related to the basal ganglia and to the presumed parkinsonian features of these mice.
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Imperatorin is a furanocoumarin compound which exists in many medicinal herbs and possesses various biological activities. Herein, we investigated the antiallergic effects of imperatorin in asthmatic mice and explored the immunomodulatory actions of imperatorin on immune cells. We used a murine model of ovalbumin (OVA)-induced asthma to evaluate the therapeutic potential of imperatorin. ⋯ Additionally, imperatorin directly suppressed activated CD4(+) T-cell proliferation and cytokine production. Imperatorin may possess therapeutic potential against Th2-mediated allergic asthma not only via stimulating DC induction of Tregs but also via direct inhibition of Th2 cell activation. These findings provide new insights into how imperatorin affects the Th2 immune response and the development of imperatorin as a Treg-type immunomodulatory agent to treat allergic asthma.
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N-acylethanolamines (NAEs) comprise a family of bioactive lipid molecules present in animal and plant tissues, with N-palmitoylethanolamine (PEA) having received much attention owing to its anti-inflammatory, analgesic and neuroprotective activities. 2-Pentadecyl-2-oxazoline (PEA-OXA), the oxazoline of PEA, reportedly modulates activity of N-acylethanolamine-hydrolyzing acid amidase (NAAA), which catabolizes PEA. Because PEA is produced on demand and exerts pleiotropic effects on non-neuronal cells implicated in neuroinflammation, modulating the specific amidases for NAEs (NAAA in particular) could be a way to preserve PEA role in maintaining cellular homeostasis through its rapid on-demand synthesis and equally rapid degradation. This study provides the first description of PEA-OXA in both green and roasted coffee beans and Moka infusions, and its synthesis. ⋯ PEA-OXA markedly reduced also the increase in hindpaw myeloperoxidase activity, an index of polymorphonuclear cell accumulation in inflammatory tissues. NAAA modulators like PEA-OXA may serve to maximize availability of NAEs (e.g. PEA) while providing for recycling of the NAE components for further resynthesis.
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The alpha2-adrenergic receptor agonist Dexmedetomidine (Dex) is a sedative medication used by anesthesiologists. Dex protects the heart against ischemia-reperfusion (IR) and can also act as a preconditioning mimetic. The mechanisms involved in Dex-dependent cardiac preconditioning, and whether this action occurs directly or indirectly on cardiomyocytes, still remain unclear. ⋯ Cardiomyocyte death was attenuated by co-culturing them with endothelial cells pre-treated with Dex. In summary, our results show that Dex triggers cardiac protection by activating the eNOS/NO signaling pathway. This pharmacological effect of Dex requires its interaction with the endothelium.
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These studies probed the relationship between intrinsic efficacy and tolerance/cross-tolerance between ∆(9)-THC and synthetic cannabinoid drugs of abuse (SCBs) by examining in vivo effects and cellular changes concomitant with their repeated administration in mice. Dose-effect relationships for hypothermic effects were determined in order to confirm that SCBs JWH-018 and JWH-073 are higher efficacy agonists than ∆(9)-THC in mice. Separate groups of mice were treated with saline, sub-maximal hypothermic doses of JWH-018 or JWH-073 (3.0mg/kg or 10.0mg/kg, respectively) or a maximally hypothermic dose of 30.0mg/kg ∆(9)-THC once per day for 5 consecutive days while core temperature and locomotor activity were monitored via biotelemetry. ⋯ Select brain regions from chronically treated mice were examined for changes in CB1 receptor expression and function. Expression and function of hypothalamic CB1Rs were reduced in mice receiving chronic drugs, but cortical CB1R expression and function were not altered. Collectively, these data demonstrate that repeated ∆(9)-THC, JWH-018 and JWH-073 can induce long-lasting tolerance to some in vivo effects, which is likely mediated by region-specific downregulation and desensitization of CB1Rs.