ABSTRACT
Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports a potent covalent MAGL inhibitor, SAR127303. The compound behaves as a selective and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG in mice. In vivo, SAR127303 produces antinociceptive effects in assays of inflammatory and visceral pain. In addition, the drug alters learning performance in several assays related to episodic, working and spatial memory. Moreover, long term potentiation (LTP) of CA1 synaptic transmission and acetylcholine release in the hippocampus, two hallmarks of memory function, are both decreased by SAR127303. Although inactive in acute seizure tests, repeated administration of SAR127303 delays the acquisition and decreases kindled seizures in mice, indicating that the drug slows down epileptogenesis, a finding deserving further investigation to evaluate the potential of MAGL inhibitors as antiepileptics. However, the observation that 2-AG hydrolysis blockade alters learning and memory performance, suggests that such drugs may have limited value as therapeutic agents.
Subject(s)
Analgesics/pharmacology , Arachidonic Acids/metabolism , Carbamates/pharmacology , Endocannabinoids/metabolism , Glycerides/metabolism , Learning/drug effects , Memory, Short-Term/drug effects , Monoacylglycerol Lipases/metabolism , Sulfonamides/pharmacology , Acetylcholine/metabolism , Administration, Oral , Analgesics/chemistry , Analgesics/therapeutic use , Animals , Arachidonic Acids/chemistry , Binding Sites , Brain/metabolism , Cannabinoid Receptor Antagonists/pharmacology , Carbamates/chemistry , Carbamates/therapeutic use , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Disease Models, Animal , Electric Stimulation , Endocannabinoids/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Glycerides/chemistry , Hippocampus/drug effects , Hippocampus/metabolism , Humans , Hydrolysis , In Vitro Techniques , Long-Term Potentiation/drug effects , Mass Spectrometry , Mice , Mice, Inbred C57BL , Mice, SCID , Monoacylglycerol Lipases/antagonists & inhibitors , Pain/drug therapy , Pain/pathology , Piperidines/pharmacology , Protein Structure, Tertiary , Pyrazoles/pharmacology , Rimonabant , Seizures/drug therapy , Seizures/pathology , Sulfonamides/chemistry , Sulfonamides/therapeutic useABSTRACT
AIM: The aim was to review the use and indications of cultured autologous epidermis (CAE) in extensive burns and to evaluate the efficiency of our strategy of burn treatment. MATERIALS AND METHODS: This retrospective study comprised 15 years (1997-2012). INCLUSION CRITERIA: all patients who received CAE. EXCLUSION CRITERIA: patients who died before complete healing and patients who received exclusively cultured allogeneic keratinocytes. Evaluation criteria were clinical. Time and success of wound healing after CAE graft were evaluated. RESULTS: A total of 63 patients were included with severity Baux score of 107 (from 70 to 140) and mean percentage of TBSA of 71% (from 40% to 97%). The CAE were used as Cuono method, in STSG donor sites and deep 2nd degree burns and in combination with large-meshed STSG (1:6-1:12) in extensively burned patients. Cuono method was used in 6 patients. The final take was 16% (0-30) because of the great fragility of the obtained epidermis. Nine patients with deep 2nd degree burns (mean TBSA 81%, from 60 to 97%) were successfully treated with only CAE without skin grafting. Combined technique (STSG meshed at 1:6-1:12 covered with CAE) was used in 27 patients (mean TBSA 69%, from 49% to 96%) with 85% success rate. Finally, donor sites treated with CAE in 49 patients could be harvested several times thanks to rapid epithelialization (time of wound healing was 7 days (from 5 to 10 days)). CONCLUSION: The CAE allow rapid healing of STSG donor sites and deep 2nd second degree burns in extensively burned patients.
Subject(s)
Burns/surgery , Cells, Cultured/transplantation , Epidermis/transplantation , Keratinocytes/transplantation , Adolescent , Adult , Cell Culture Techniques , Female , Humans , Male , Retrospective Studies , Skin Transplantation , Skin, Artificial , Transplantation, Autologous , Treatment Outcome , Wound Healing , Young AdultABSTRACT
Spinal cord injury is frequently followed by the loss of supraspinal control of sensory, autonomic and motor functions at the sublesional level. In order to enhance recovery in spinal cord-injured patients, we have developed three fundamental strategies in experimental models. These strategies define in turn three chronological levels of postlesional intervention in the spinal cord. Neuroprotection soon after injury using pharmacological tools to reduce the progressive secondary injury processes that follow during the first week after the initial lesion. This strategy was conducted up to clinical trials, showing that a pharmacological therapy can reduce the permanent neurological deficit that usually follows an acute injury of the central nervous system (CNS). A second strategy, which is initiated not long after the lesion, aims at promoting axonal regeneration by acting on the main barrier to regeneration of lesioned axons: the glial scar. Finally a mid-term substitutive strategy is the management of the sublesional spinal cord by sensorimotor stimulation and/or supply of missing key afferents, such as monoaminergic systems. These three strategies are reviewed. Only a combination of these different approaches will be able to provide an optimal basis for potential therapeutic interventions directed to functional recovery after spinal cord injury.
