Minocycline decreases in vitro microglial motility, beta1-integrin, and Kv1.3 channel expression.
Minocycline is a semisynthetic, tetracycline derivative that exerts anti-inflammatory and neuroprotective effects unrelated to its anti-microbial action. We have previously shown that minocycline prevented peripheral nerve injury-induced mechanical allodynia. Minocycline's mechanisms of action as a neuroprotective and anti-allodynic agent are unknown. In response to injury, microglia become activated, proliferate, and migrate. Resting microglia express voltage-dependent inward K(+) currents and blocking Kv1.3 channels has been shown to inhibit microglial-mediated neuronal death. We investigated the effect of minocycline on the expression of Kv channels, cell motility, and beta-integrin expression using primary rat cortical microglia, transwell assays, and by flow cytometry. Minocycline significantly reduced microglial migration to cellular debris, astrocyte-conditioned medium, ADP, and algesic mediators and significantly reduced the expression of CD29 (beta(1)-integrin) but not CD18 (beta(2)-integrin). Minocycline reduced the effect of extracellular potassium and later decreased microglial Kv1.3 expression. In summary, we uncovered a novel effect of minocycline that demonstrates this agent decreases microglial beta(1)-integrin expression, which leads to inhibition of motility. We propose an in vivo model whereby reduced microglial trafficking to injured neurons following nerve injury decreases the release of proinflammatory mediators into the synaptic milieu, preventing neuronal sensitization, the pathological correlate to chronic pain.
Nutile-McMenemy
Nancy
N
Department of Anesthesiology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA.
Elfenbein
Arye
A
Deleo
Joyce A
JA
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018925:Chemokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D018698:Glutamic Acid / Q000494:pharmacology; D019012:Integrin beta1 / Q000378:metabolism*; D051664:Kv1.3 Potassium Channel / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D017628:Microglia / Q000187:drug effects*; D008911:Minocycline / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012604:Scorpion Venoms / Q000494:pharmacology
D015703:Antigens, CD; D018925:Chemokines; D019012:Integrin beta1; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms; D018698:Glutamic Acid; C077910:margatoxin; D008911:Minocycline