Evidence indicating that statins have anti-inflammatory and immunomodulatory effects, apparently manifested by decreased levels of C-reactive protein (CRP), has led to suggestions that these agents might represent an effective treatment approach in patients with rheumatoid arthritis (RA). While conflicting evidence has emerged regarding this particular application, the possibility that statin use might help prevent the onset of RA continues to be investigated. A large retrospective analysis of over 200,000 patients enrolled in an Israeli health maintenance organization suggests that persistent statin use may indeed have a protective effect against RA.

To minimize the effect of healthy user bias, the association between statin persistence and onset of osteoarthritis (OA)—a disease deemed unlikely to be affected by statin use—was also calculated. Persistent statin use was categorized as the proportion of days covered (PDC), defined as the quantity of dispensed statins divided by the interval between the first purchase of the drug and a diagnosis of RA or OA, death, or the end of the study.

The crude incident density rate of RA among nonpersistent statin users (PDC <20%) was 51% greater than in highly persistent users (PDC ≥80%). After adjustment for confounding variables, highly persistent users had a hazard ratio (HR) for RA of 0.58 (95% CI 0.52–0.65) compared with nonpersistent users. For comparison, the corresponding HR for OA incidence showed a far more modest decrease in risk associated with persistent statin use (HR 0.85, 95% CI 0.81–0.88).

These findings indicate that further prospective, controlled studies are warranted to elucidate this association between statin use and protection against RA onset.

source: nature

Endocannabinoids are released by neurons and are generally thought to inhibit synaptic transmission in many brain regions, including the hippocampus. Recent studies showed that in this region, both neurons and astrocytes express endocannabinoid 1 receptors (CB1Rs), but the role of astrocytic CB1Rs on synaptic transmission has remained unknown. Now, Navarrete and Araque show that endocannabinoid activation of astrocytic CB1Rs potentiates neurotransmission at synapses far away from the site of endocannabinoid release.

The authors first showed that in hippocampal slices, neuronal depolarization could evoke both suppression of excitation (depolarization-induced suppression of excitation (DSE)) and potentiation of transmitter release at synapses in an adjacent neuron. Both effects were blocked by inhibition of endocannabinoid release from the postsynaptic neuron with BAPTA or by perfusing hippocampal slices with a CB1R antagonist, indicating that endocannabinoids mediate both DSE and synaptic potentiation (endocannabinoid-mediated synaptic potentiation (eSP)).

The authors next examined whether DSE and eSP are mediated by neuronal and/or astrocytic CB1Rs. Activation of CB1Rs on astrocytes is known to increase intracellular Ca²⁺ levels, and depleting intracellular Ca²⁺ from astrocytes abolished eSP but not DSE. In astrocytes, Ca²⁺ elevation induces glutamate release, which subsequently activates mGluRs on presynaptic neurons and so potentiates neurotransmitter release. The authors showed that perfusing hippocampal slices with an antagonist of group I mGluRs blocked eSP, indicating that this pathway also underlies endocannabinoid-mediated synaptic potentiation. Activation of neuronal CB1Rs activates G_i/o proteins, which are sensitive to pertussis toxin. Treating hippocampal slices with this toxin inhibited endocannabinoid-mediated DSE but increased eSP. Together, these findings show that neuronal CB1Rs mediate DSE, whereas astrocytic CB1Rs — and subsequently neuronal mGluRs — mediate eSP.

If endocannabinoids released by a neuron can induce both potentiation and inhibition of transmission at other hippocampal synapses by activating CB1Rs, what determines the direction of the modulation? The authors showed that applying a CB1R agonist reduced the efficacy of eSP induced by neuronal depotentiation. This suggests that synapses showing eSP do express CB1Rs but that these receptors are not activated by endocannabinoids released from an activated neuron, perhaps because the endocannabinoids cannot reach them. Indeed, the authors found that DSE occurred at synapses located near the stimulated neuron, whereas eSP was only found at synapses further away. This is in agreement with previous findings that Ca²⁺ elevation induced in astrocytes by depolarization of a nearby neuron can spread through the cell and thereby have effects at some distance from the stimulated neuron.

This study showed that endocannabinoids released by neurons activate CB1Rs on nearby neurons, with short-range, inhibitory effects, and CB1Rs on astrocytes, which leads to Ca²⁺ elevation and subsequent astrocytic glutamate release, stimulation of presynaptic glutamate receptors and synaptic potentiation at more distant sites. These findings provide further insight into the role of astrocytes in synaptic plasticity.

source: nature neuroscience