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Cannabinoid control of neuroinflammation related to multiple sclerosis.

ABSTRACT: The cannabis plant (Cannabis sativa) has been known by many names but the question remains 'Can we call it medicine?' There has been renewed interest in the value of cannabis for the control of neuroinflammatory conditions such as multiple sclerosis, where it has been shown to have some effect on spasticity and pain both experimentally and in clinical trials in humans. However, in addition to symptom control potential, the question remains whether cannabinoids can modify the neuroinflammatory element which drives relapsing neurological attacks and the accumulation of progressive disability. In experimental studies it has been recently shown that synthetic cannabinoids can affect the immune response both indirectly via CB1 receptor-mediated signalling nerve centres controlling the systemic release of immunosuppressive molecules and directly by CB2 receptor-mediated inhibition of lymphocyte and macrophage/microglial cell function. However, these immunosuppressive possibilities that would limit the frequency of relapsing attacks will probably not be realized clinically, following use of medical cannabis, due to dose constraints. However, cannabinoids may still affect the glial response within the damaged central nervous system, which facilitate the slow, neurodegenerative processes that account for progressive neurodegeneration, and therefore may have utility in addition to value of cannabis-related drugs for symptom control.

SUBMITTER: Baker D

PROVIDER: S-EPMC2190016 | biostudies-other | 2007 Nov

REPOSITORIES: biostudies-other

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Project description:BackgroundDepression, a condition commonly comorbid with multiple sclerosis (MS), is associated more generally with elevated inflammatory markers and hippocampal pathology. We hypothesized that neuroinflammation in the hippocampus is responsible for depression associated with MS. We characterized the relationship between depressive symptoms and hippocampal microglial activation in patients with MS using the 18-kDa translocator protein radioligand [(18)F]PBR111. To evaluate pathophysiologic mechanisms, we explored the relationships between hippocampal neuroinflammation, depressive symptoms, and hippocampal functional connectivities defined by resting-state functional magnetic resonance imaging.MethodsThe Beck Depression Inventory (BDI) was administered to 11 patients with MS and 22 healthy control subjects before scanning with positron emission tomography and functional magnetic resonance imaging. We tested for higher [(18)F]PBR111 uptake in the hippocampus of patients with MS relative to healthy control subjects and examined the correlations between [(18)F]PBR111 uptake, BDI scores, and hippocampal functional connectivities in the patients with MS.ResultsPatients with MS had an increased hippocampal [(18)F]PBR111 distribution volume ratio relative to healthy control subjects (p = .024), and the hippocampal distribution volume ratio was strongly correlated with the BDI score in patients with MS (r = .86, p = .006). Hippocampal functional connectivities to the subgenual cingulate and prefrontal and parietal regions correlated with BDI scores and [(18)F]PBR111 distribution volume ratio.ConclusionsOur results provide evidence that hippocampal microglial activation in MS impairs the brain functional connectivities in regions contributing to maintenance of a normal affective state. Our results suggest a rationale for the responsiveness of depression in some patients with MS to effective control of brain neuroinflammation. Our findings also lend support to further investigation of the role of inflammatory processes in the pathogenesis of depression more generally.

Project description:BACKGROUND:Autonomic nervous system dysfunction has been previously observed in multiple sclerosis (MS) patients. OBJECTIVE:To assess associations between magnetic resonance imaging-detected neuroinflammatory and neurodegenerative pathology and postural venous flow changes indicative of autonomic nervous system function. METHODS:We used a standardized 3T magnetic resonance imaging protocol to scan 138 patients with MS and 49 healthy controls. Lesion volume and brain volumes were assessed. The cerebral venous flow (CVF) was examined by color-Doppler sonography in supine and upright positions and the difference was calculated as ?CVF. Based on ?CVF, subjects were split into absolute or quartile groups. Student's t test, ?2-test, and analysis of covariance adjusted for age and sex were used accordingly. Benjamini-Hochberg procedure corrected the p-values for multiple comparisons. RESULTS:No differences were found between healthy controls and patients with MS in both supine and upright Doppler-derived CVF, nor in prevalence of abnormal postural venous control. Patients with absolute negative ?CVF had higher disability scores (p?=?0.013), lower gray matter (p?=?0.039) and cortical (p?=?0.044) volumes. The negative ?CVF MS group also showed numerically worse bladder/bowel function when compared to the positive ?CVF (2.3 vs. 1.5, p?=?0.052). Similarly, the lowest quartile ?CVF MS group had higher T1-lesion volumes (p?=?0.033), T2-lesion volumes (p?=?0.032), and lower deep gray matter (p?=?0.043) and thalamus (p?=?0.033) volumes when compared to those with higher ?CVF quartiles. CONCLUSION:No difference in postural venous outflow between patients with MS and healthy controls was found. However, when the abnormal ?CVF is present within the MS population, it may be associated with more inflammatory and neurodegenerative pathology. Further studies should explore whether the orthostatic venous changes are an aging or an MS-related phenomenon and if the etiology is due to impaired autonomic nervous system functioning.

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Cannabinoid control of neuroinflammation related to multiple sclerosis.

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