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Biotech / Medical : Neurobiological Tech (NTII) -- Ignore unavailable to you. Want to Upgrade?

To: Craig S. Owens who wrote (612)	7/18/1999 11:32:00 AM
From: Dr. John M. de Castro	Read Replies (1) \| Respond to of 1494

Just when you thought it was safe to read the thread again, he's back with more boring abstracts. Actually this is an excellent in vitro study of the process by which AIDS producers dementia and how memantine can block the process. Happy reading! John de C Role of Na+/H+ exchangers, excitatory amino acid receptors and voltage-operated Ca2+ channels in human immunodeficiency virus type 1 gp120-mediated increases in intracellular Ca2+ in human neurons and astrocytes. Holden CP, Haughey NJ, Nath A, Geiger JD, Neuroscience 1999;91(4):1369-78 Department of Pharmacology and Therapeutics, University of Manitoba Faculty of Medicine, Winnipeg, Canada. Human immunodeficiency virus type 1 (HIV-1) dementia is the commonest form of dementia in North American people less than 60 years of age. HIV-1 envelope glycoprotein gp120 has been implicated in the neurotoxicity observed in, and the pathogenesis of, HIV-1 dementia. Recombinant gp120 (gp120) was pressure-applied on to cultured human fetal neurons and astrocytes and, by using single-cell calcium imaging, we determined the mechanisms responsible for gp120-induced increases in the levels of intracellular calcium ([Ca2+]i). Significant dose-related increases in [Ca2+]i were observed in neurons and astrocytes. In neurons, 5 pM gp120 increased [Ca2+]i by 290+/-13 nM and increases of 2210+/-211 nM were found at 209 nM, the highest concentration of gp120 tested. The apparent EC50 value for gp120 of 223+/-40 pM in neurons was not significantly different from that in astrocytes. Immunoelution of gp120 with polyclonal anti-gp120 and Ca2+-free conditions blocked increases in [Ca2+]i by gp120. Increases in [Ca2+]i were significantly (P < 0.005) attenuated by the Na+/H+ exchange blocker 5-(N-methyl-N-isobutyl)-amiloride in neurons and astrocytes. The L-type calcium channel blockers nimodipine, diltiazem and CdCl2 + NiCl2 significantly (P < 0.005) reduced increases in [Ca2+]i in neurons, but not astrocytes. Increases in [Ca2+]i by gp120 were not significantly affected by blockers of N-, P- and Q-type calcium channels. The N-methyl-D-aspartate receptor antagonists +/-)-2-amino-5-phosphonopentanoic acid (AP5), memantine and dizocilpine significantly (P < 0.01) lowered gp120-induced increases in [Ca2+]i in neurons. AP5 and memantine, but not dizocilpine, significantly (P < 0.01) reduced increases in [Ca2+]i by gp120 in astrocytes. Gp120 appears to activate astrocyte Na+/H+ exchangers to release glutamate and potassium and, subsequent to this, increases in [Ca2+]i in neurons and astrocytes result from activation of excitatory amino acid receptors on astrocytes and neurons, and voltage-operated calcium channels on neurons. Drugs that block gp120-induced changes in [Ca2+]i in neurons and astrocytes may help in the treatment of HIV-1 dementia.

To: Craig S. Owens who wrote (612)	7/18/1999 11:40:00 AM
From: Dr. John M. de Castro	Respond to of 1494

This is a nice study of the pharmocdynamics of memantine. It shows that memantine is taken up and concentrated in brain tissue when administered peripherally. Getting into the brain is often a major obstacle for a drug. This study unequivocally demonstrates that the blood brain barrier is no obstacle at all for memantine. It's also nice to see that Merz is coming out of its shell and publishing its findings for the world to see. Best regards John de C Brain penetration and in vivo recovery of NMDA receptor antagonists amantadine and memantine: a quantitative microdialysis study. Pharm Res 1999 May;16(5):637-42 Hesselink MB, De Boer BG, Breimer DD, Danysz W, Department of Pharmacological Research, Merz + Co., Frankfurt/Main, Germany. PURPOSE: To determine free brain concentrations of the clinically used uncompetitive NMDA antagonists memantine and amantadine using microdialysis corrected for in vivo recovery in relations to serum, CSF and brain tissue levels and their in vitro potency at NMDA receptors. METHODS: Microdialysis corrected for in vivo recovery was used to determine brain ECF concentrations after steady-state administration of either memantine or amantadine. Additionally CSF, serum, and brain tissue were analyzed. RESULTS: Following 7 days of infusion of memantine or amantadine (20 and 100 mg/kg/day respectively) whole brain concentrations were 44-and 16-fold higher than free concentrations in serum respectively. The free brain ECF concentration of memantine (0.83 +/- 0.05 microM) was comparable to free serum and CSF concentrations. In case of amantadine, it was lower. A higher in vivo than in vitro recovery was found for memantine. CONCLUSIONS: At clinically relevant doses memantine reaches a brain ECF concentration in range of its affinity for the NMDA receptor and close to its free serum concentration. This is not the case for amantadine and different mechanisms of action may be operational.