Inflammation-reactive astrocytes can be restored with a three drug combination

Abstract

Abstract Aims In inflammation-reactive astrocytes the cell parameters, Ca2+ signalling, Na+ transporters, cytoskeleton, and release of proinflammatory cytokines are affected. We want to re-establish these parameters with agents, which might have a potential to restore the cells back to a normal non-inflammatory level. Methods Astrocytes in primary cultures were incubated with lipopolysaccharide (LPS) (10 ng/ml) for 24 h to become inflammation-reactive. Different parameters were analysed to verify this inflammation: Ca2+ signalling, Na+/K+-ATPase expression, actin filament organization, and interleukin-1beta release (IL-1β). Results We have used an opioid agonist, endomorphin-1, that stimulates the Gi/o protein of the μ-opioid receptor, an opioid antagonist, naloxone, that inhibits the Gs protein of the μ-opioid receptor in ultralow concentrations, and an anti-epileptic agent, levetiracetam, that counteracts the release of IL-1β. The combination of these three agents managed to activate the Gi/o protein and Na+/K+-ATPase activity, inhibit the Gs protein, and decrease the release of IL-1β. The disorganized actin filaments were restored. Conclusions The findings that the important cell parameters in astrocytes were restored back to their normal non-inflammatory state after the cells were treated with the inflammatory agent LPS could be of clinical significance. It may be useful for the treatment of neuroinflammation and also maybe of long-term pain. The astrocyte networks play a significant role and therefore a well-working intercellular Ca2+ signalling is of utmost importance. Significance These findings put new potential drug regimens towards treatment of neuroinflammation and long-term pain into focus.