Evolutionism

Received June 11, 2006

Abstract:

Alzheimer's disease is the leading cause of dementia among the elderly, and with the ever-increasing size of this population, cases of Alzheimer's disease are expected to triple over the next 50 years. Consequently, the development of treatments that slow or halt the disease progression have become imperative to both improve the quality of life for patients and reduce the health care costs attributable to Alzheimer's disease. Here, we demonstrate that the active component of marijuana, ⁹-tetrahydrocannabinol (THC), competitively inhibits the enzyme acetylcholinesterase (AChE) as well as prevents AChE-induced amyloid -peptide (A) aggregation, the key pathological marker of Alzheimer's disease. Computational modeling of the THC-AChE interaction revealed that THC binds in the peripheral anionic site of AChE, the critical region involved in amyloidgenesis. Compared to currently approved drugs prescribed for the treatment of Alzheimer's disease, THC is a considerably superior inhibitor of A aggregation, and this study provides a previously unrecognized molecular mechanism through which cannabinoid molecules may directly impact the progression of this debilitating disease.

Keywords: Cannabinoids; Alzheimer's disease; acetylcholinesterase

Journal Article

Endocannabinoids and β-amyloid-induced neurotoxicity in vivo: effect of pharmacological elevation of endocannabinoid levels Journal Cellular and Molecular Life Sciences (CMLS) Publisher Birkhäuser Basel ISSN 1420-682X (Print) 1420-9071 (Online) Issue Volume 63, Number 12 / June, 2006 Category Research Article DOI 10.1007/s00018-006-6037-3 Pages 1410-1424 Subject Collection Biomedical and Life Sciences SpringerLink Date Saturday, May 27, 2006

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M. van der Stelt1, 5, C. Mazzola2, G. Esposito3, I. Matias1, S. Petrosino1, D. De Filippis3, V. Micale2, L. Steardo4, F. Drago2, T. Iuvone3 and V. Di Marzo1  (1)  Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R. Pozzuoli, Naples, Italy (2)  Department of Experimental and Clinical Pharmacology, University of Catania Medical School, Catania, Italy (3)  Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy (4)  Department of Human Physiology and Pharmacology, ‘V. Espamer’, University of Rome ‘La Sapienza’, Rome, Italy (5)  Present address: NV Organon, PO Box 20, 5340 BH Oss, The Netherlands Published online: 29 May 2006 Abstract.  We investigated the involvement of endocannabinoids in the control of neuronal damage and memory retention loss in rodents treated with the β-amyloid peptide (1–42) (BAP). Twelve days after stereotaxic injection of BAP into the rat cortex, and concomitant with the appearance in the hippocampus of markers of neuronal damage, 2-arachidonoyl glycerol, but not anandamide, levels were enhanced in the hippocampus. VDM-11 (5 mg/kg, i.p.), an inhibitor of endocannabinoid cellular reuptake, significantly enhanced rat hippocampal and mouse brain endocannabinoid levels when administered sub-chronically starting either 3 or 7 days after BAP injection and until the 12–14th day. VDM-11 concomitantly reversed hippocampal damage in rats, and loss of memory retention in the passive avoidance test in mice, but only when administered from the 3rd day after BAP injection. We suggest that early, as opposed to late, pharmacological enhancement of brain endocannabinoid levels might protect against β-amyloid neurotoxicity and its consequences. Keywords.  Anandamide - 2-arachidonoyl glycerol - cannabinoid - memory - receptor - neuroprotection - apoptosis Received 26 January 2006; received after revision 24 March 2006; accepted 12 April 2006 V. Di Marzo Email: vdimarzo@icmib.na.cnr.it Fax: +39 081 8041770