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Biotech / Medical : Indications -- obesity/erectile dysfunction

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From: scaram(o)uche1/20/2018 11:38:14 AM
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Br J Pharmacol. 2018 Jan 16. doi: 10.1111/bph.14147. [Epub ahead of print]

Single and combined effects of plant-derived (THC, CBD) and synthetic (WIN-55,212) cannabinoids on cognition and cannabinoid-associated withdrawal signs in mice.

Myers AM, Siegele PB, Foss JD, Tuma RF, Ward SJ.

Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.

BACKGROUND AND PURPOSE:
It has been suggested that the non-euphorogenic phytocannabinoid cannabidiol (CBD) can ameliorate adverse effects of delta-9-tetrahydrocannabinol (THC). We determined whether CBD ameliorates cognitive deficits and withdrawal signs induced by cannabinoid CB1/CB2 receptor agonists or produces these pharmacological effects on its own.

EXPERIMENTAL APPROACH:
The effects of THC or the CB1/CB2 receptor full agonist WIN55212 (WIN) alone, CBD alone, or their combination were tested across a range of doses. Cognitive effects were assessed in C57BL/6 mice in a conditional discrimination task and in the Barnes maze. Cannabinoid withdrawal signs were assessed following precipitated withdrawal by acute administration of the CB1 antagonist SR141716, the 5-HT1A receptor antagonist WAY100635, the TRPV1 receptor antagonist capsazepine, or the adenosine A2A receptor antagonist SCH58261.

KEY RESULTS:
THC produced significant motor and cognitive impairment in the Barnes maze task, and none of these deficits were attenuated by the addition of CBD. CBD alone did not impact cognitive performance. Precipitation of withdrawal signs by SR141716 occurred in mice chronically treated with THC or WIN, and these withdrawal signs were not attenuated by addition of chronic CBD. Chronic treatment with CBD alone did not induce withdrawal signs precipitated by SR141716 or WAY100635. Chronic CBD treatment also produced anxiolysis and this was not altered by attempting to precipitate withdrawal-induced anxiety with a range of antagonists.

CONCLUSIONS AND IMPLICATIONS:
These data suggest that CBD as a monotherapy may prove to be a safer pharmacological agent for the treatment of several disorders as compared with CB1 agonism alone or in combination with CBD.

Epilepsia. 2018 Jan;59(1):79-91. doi: 10.1111/epi.13950. Epub 2017 Nov 24.

Inhibition of monoacylglycerol lipase terminates diazepam-resistant status epilepticus in mice and its effects are potentiated by a ketogenic diet.

Terrone G1, Pauletti A1, Salamone A1, Rizzi M1, Villa BR1, Porcu L2, Sheehan MJ3, Guilmette E3, Butler CR4, Piro JR3, Samad TA3, Vezzani A1.

1
Department of Neuroscience, IRCCS-Mario Negri Institute for Pharmacological Research, Milano, Italy.
2
Department of Oncology, IRCCS-Mario Negri Institute for Pharmacological Research, Milano, Italy.
3
Internal Medicine Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA, USA.
4
Medicinal Chemistry, Pfizer Worldwide Research & Development, Cambridge, MA, USA.

OBJECTIVE:
Status epilepticus (SE) is a life-threatening and commonly drug-refractory condition. Novel therapies are needed to rapidly terminate seizures to prevent mortality and morbidity. Monoacylglycerol lipase (MAGL) is the key enzyme responsible for the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) and a major contributor to the brain pool of arachidonic acid (AA). Inhibiting of monoacylglycerol lipase modulates synaptic activity and neuroinflammation, 2 mediators of excessive neuronal activation underlying seizures. We studied the effect of a potent and selective irreversible MAGL inhibitor, CPD-4645, on SE that was refractory to diazepam, its neuropathologic sequelae, and the mechanism underlying the drug's effects.

METHODS:
Diazepam-resistant SE was induced in adult mice fed with standard or ketogenic diet or in cannabinoid receptor type 1 (CB1) receptor knock-out mice. CPD-4645 (10 mg/kg, subcutaneously) or vehicle was dosed 1 and 7 h after status epilepticus onset in video-electroencephalography (EEG) recorded mice. At the end of SE, mice were examined in the novel object recognition test followed by neuronal cellloss analysis.

RESULTS:
CPD-4645 maximal plasma and brain concentrations were attained 0.5 h postinjection (half-life = 3.7 h) and elevated brain 2-AG levels by approximately 4-fold. CPD-4645 administered to standard diet-fed mice progressively reduced spike frequency during 3 h postinjection, thereby shortening SE duration by 47%. The drug immediately abrogated SE in ketogenic diet-fed mice. CPD-4645 rescued neuronal cell loss and cognitive deficit and reduced interleukin (IL)-1ß and cyclooxygenase 2 (COX-2) brain expression resulting from SE. The CPD-4645 effect on SE was similar in mice lacking CB1 receptors.

SIGNIFICANCE:
MAGL represents a novel therapeutic target for treating status epilepticus and improving its sequelae. CPD-4645 therapeutic effects appear to be predominantly mediated by modulation of neuroinflammation.
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