Diazepam inhibits HIV-1 Tat-induced migration of human microglia.
During HIV-1 encephalitis, the chemotaxis-inducing activity of Tat may enhance the viral life cycle through recruitment of additional susceptible microglial cells to foci of infection. Benzodiazepines (BDZs) readily penetrate the blood-brain barrier and are known to possess anti-inflammatory properties. Pretreatment of human microglial cells with peripheral (Ro5-4864) and mixed (diazepam), but not central (clonazepam), benzodiazepine receptor ligands was found to potently suppress HIV-1 Tat-induced chemotaxis. Application of Tat to microglial cells evokes an increase in intracellular calcium concentration ([Ca(2+)]i) that rapidly desensitizes the cells. Diazepam's inhibitory effect was associated with its ability to block Tat-induced [Ca(2+)]i mobilization. These data support the notion that through their effects on microglia, peripheral BDZ receptor ligands could alter the neuropathogenesis of HIV-1.
Lokensgard
J R
JR
Neuroimmunology Laboratory, Minneapolis Medical Research Foundation, Minneapolis, Minnesota 55404, USA. loken006@tc.umn.edu
Hu
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Hegg
C C
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Thayer
S A
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Gekker
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Peterson
P K
PK
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects*; D002633:Chemotaxis / Q000187:drug effects*; D002998:Clonazepam / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology*; D015696:Gene Products, tat / Q000037:antagonists & inhibitors* / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D017628:Microglia / Q000187:drug effects* / Q000821:virology; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000235:genetics; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus
D000276:Adjuvants, Immunologic; D001570:Benzodiazepinones; D015696:Gene Products, tat; D009419:Nerve Tissue Proteins; D019713:Receptors, CCR5; D011963:Receptors, GABA-A; D054322:tat Gene Products, Human Immunodeficiency Virus; C028513:4'-chlorodiazepam; D002998:Clonazepam; D003975:Diazepam