Abstract
Genetic ablation of type-1 cannabinoid receptors (CB1Rs) exacerbates the neurodegenerative damage of experimental autoimmune encephalomyelitis, the rodent model of multiple sclerosis (MS). To address the role on CB1Rs in the pathophysiology of human MS, we first investigated the impact of AAT trinucleotide short tandem repeat polymorphism of CNR1 gene on CB1R cell expression, and secondly on the inflammatory neurodegeneration process responsible for irreversible disability in MS patients. We found that MS patients with long AAT repeats within the CNR1 gene (≥12 in both alleles) had more pronounced neuronal degeneration in response to inflammatory white matter damage both in the optic nerve and in the cortex. Optical Coherence Tomography (OCT), in fact, showed more severe alterations of the retinal nerve fiber layer (RNFL) thickness and of the macular volume (MV) after an episode of optic neuritis in MS patients carrying the long AAT genotype of CNR1. MS patients with long AAT repeats also had magnetic resonance imaging (MRI) evidence of increased gray matter damage in response to inflammatory lesions of the white matter, especially in areas with a major role in cognition. In parallel, visual abilities evaluated at the low contrast acuity test, and cognitive performances were negatively influenced by the long AAT CNR1 genotype in our sample of MS patients. Our results demonstrate the biological relevance of the (AAT)n CNR1 repeats in the inflammatory neurodegenerative damage of MS.
Highlights
Type-1 cannabinoid receptors (CB1Rs) are among the most abundant G protein-coupled receptors in the mammalian brain [1,2,3], where they play a pivotal role in the control of synaptic transmission [4], and in the maintenance of neuronal integrity [5,6]
Total binding (TB) of cell extracts was quantified, and was compared to the nonspecific binding (NSB) of the same samples reacted with anti-CB1R antibodies that had been pre-incubated with the blocking peptide
The dose-dependence curves of TB, NSB, and SB of different amounts of CHO-CB1R cell extracts are reported in Fig. 1A, that clearly shows the specificity of the anti-CB1R antibodies used in this study
Summary
Type-1 cannabinoid receptors (CB1Rs) are among the most abundant G protein-coupled receptors in the mammalian brain [1,2,3], where they play a pivotal role in the control of synaptic transmission [4], and in the maintenance of neuronal integrity [5,6]. Inflammation leads to neuronal damage in the human brain, and higher frequency and severity of inflammatory episodes have been associated with accelerated neurodegeneration and disability accumulation in MS [13,14,15], but large inter-individual differences among patients exist. Based on this clinical evidence, we postulated that genetic differences in CB1R expression and function might contribute to differential inflammatory neurodegenerative damage in MS patients, as it occurs in EAE mice. In a previous study [18] some clinical measures of disease severity were unaffected by this microsatellite polymorphism, MS patients with primary progressive disease course were found to have more commonly long AAT repeats, in line with the idea that neurodegenerative damage can be influenced in MS by CB1Rs [18]
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