3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol and Nerve-Degeneration

Multiple sclerosis is increasingly being recognized as a neurodegenerative disease that is triggered by inflammatory attack of the CNS. As yet there is no satisfactory treatment. Using experimental allergic encephalo myelitis (EAE), an animal model of multiple sclerosis, we demonstrate that the cannabinoid system is neuroprotective during EAE. Mice deficient in the cannabinoid receptor CB1 tolerate inflammatory and excitotoxic insults poorly and develop substantial neurodegeneration following immune attack in EAE. In addition, exogenous CB1 agonists can provide significant neuroprotection from the consequences of inflammatory CNS disease in an experimental allergic uveitis model. Therefore, in addition to symptom management, cannabis may also slow the neurodegenerative processes that ultimately lead to chronic disability in multiple sclerosis and probably other diseases.

Topics: Animals; Aspartic Acid; Axons; Benzoxazines; Cannabinoids; Cyclohexanols; Dizocilpine Maleate; Encephalomyelitis, Autoimmune, Experimental; Excitatory Amino Acid Agonists; Gene Deletion; Humans; Mice; Mice, Transgenic; Monomeric GTP-Binding Proteins; Morpholines; Multiple Sclerosis; N-Methylaspartate; Naphthalenes; Nerve Degeneration; Nuclear Proteins; Receptors, Cannabinoid; Receptors, Drug; Receptors, N-Methyl-D-Aspartate; Retina; Saccharomyces cerevisiae Proteins; Spinal Cord; Uveitis

Topics: Action Potentials; Analgesics; Animals; Basal Ganglia; Benzoxazines; Bicuculline; Cannabinoids; Cyclohexanols; Dopamine; Dopamine Agonists; Electrophysiology; GABA Antagonists; gamma-Aminobutyric Acid; Morpholines; Motor Neurons; Naphthalenes; Nerve Degeneration; Neurotransmitter Agents; Oxidopamine; Piperidines; Pyrazoles; Quinpirole; Rats; Rimonabant; Sympatholytics; Thalamic Nuclei

The distribution and density of cannabinoid receptor binding and messenger RNA expression in aged human brain were examined in several forebrain and basal ganglia structures. In vitro binding of [3H]CP-55,940, a synthetic cannabinoid, was examined by autoradiography in fresh frozen brain sections from normal aged humans (n = 3), patients who died with Alzheimer's disease (n = 5) and patients who died with other forms of cortical pathology (n = 5). In the structures examined--hippocampal formation, neocortex, basal ganglia and parts of the brainstem--receptor binding showed a characteristic pattern of high densities in the dentate gyrus molecular layer, globus pallidus and substantia nigra pars reticulata, moderate densities in the hippocampus, neocortex, amygdala and striatum, and low densities in the white matter and brainstem. In situ hybridization histochemistry of human cannabinoid receptor, a ribonucleotide probe for the human cannabinoid receptor messenger RNA, showed a pattern of extremely dense transcript levels in subpopulations of cells in the hippocampus and cortex, moderate levels in hippocampal pyramidal neurons and neurons of the striatum, amygdala and hypothalamus, and no signal over dentate gyrus granule cells and most of the cells of the thalamus and upper brainstem, including the substantia nigra. In Alzheimer's brains, compared to normal brains, [3H]CP-55,940 binding was reduced by 37-45% in all of the subfields of the hippocampal formation and by 49% in the caudate. Lesser reductions (20-24%) occurred in the substantia nigra and globus pallidus, internal segment. Other neocortical and basal ganglia structures were not different from control levels. Levels of messenger RNA expression did not differ between Alzheimer's and control brains, but there were regionally discrete statistically significant losses of the intensely expressing cells in the hippocampus. The reductions in binding did not correlate with or localize to areas showing histopathology, estimated either on the basis of overall tissue quality or silver staining of neuritic plaques and neurofibrillary tangles. Reduced [3H]55,940 binding was associated with increasing age and with other forms of cortical pathology, suggesting that receptor losses are related to the generalized aging and/or disease process and are not selectively associated with the pathology characteristic of Alzheimer's disease, nor with overall decrements in levels of cannabinoid receptor gene expression.

Topics: Aged; Aged, 80 and over; Aging; Alzheimer Disease; Autoradiography; Brain Chemistry; Cannabinoids; Cyclohexanols; Female; Hippocampus; Humans; Image Processing, Computer-Assisted; In Situ Hybridization; Male; Memory; Middle Aged; Nerve Degeneration; Receptors, Cannabinoid; Receptors, Drug; RNA Probes; RNA, Messenger; Silver Staining