Comparison of the potency, kinetics and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo

Parsons, Chris G.; Quack, G.; Bresink, I.; Baran, L; Przegaliński, Edmund; Kostowski, Wojciech; Krząścik, Paweł; Hartmann, Sabine; Danysz, Wojciech

doi:10.1016/0028-3908(95)00092-k

Cited by 280 publications

(178 citation statements)

References 42 publications

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“…Its antiviral action results from block of the M2 small viral membrane protein (Hay, 1992). Although the utility of amantadine in treating Parkinson's disease was initially assumed to result from effects on dopaminergic systems (Danysz et al, 1997), amantadine later was found to block the channel of NMDA receptors (Kornhuber et al, 1991;Lupp et al, 1992;Parsons et al, 1995;Blanpied et al, 1997). Increasing evidence suggests that the effectiveness of amantadine in treating nervous system disorders results predominantly from its inhibition of NMDA responses (Blanchet et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Amantadine Inhibits NMDA Receptors by Accelerating Channel Closure during Channel Block

Blanpied¹,

Clarke²,

Johnson³

2005

J. Neurosci.

216

136

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The channel of NMDA receptors is blocked by a wide variety of drugs. NMDA receptor channel blockers include drugs of abuse that induce psychotic behavior, such as phencyclidine, and drugs with wide therapeutic utility, such as amantadine and memantine. We describe here the molecular mechanism of amantadine inhibition. In contrast to most other described channel-blocking molecules, amantadine causes the channel gate of NMDA receptors to close more quickly. Our results confirm that amantadine binding inhibits current flow through NMDA receptor channels but show that its main inhibitory action at pharmaceutically relevant concentrations results from stabilization of closed states of the channel. The surprising variation in the clinical utility of NMDA channel blockers may in part derive from their diverse effects on channel gating.

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Section: Introductionmentioning

confidence: 99%

Amantadine Inhibits NMDA Receptors by Accelerating Channel Closure during Channel Block

Blanpied¹,

Clarke²,

Johnson³

2005

J. Neurosci.

216

136

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“…Finally, hypomagnesaemia might be associated with an increased sensitivity to other "tmcompetitive" NMDA receptor antagonists including memantine and amantadine, drug used to treat dementia and Parkinson's Disease. 34 In summary, our results indicate that ketamine sensitivity was increased in rats rendered hypomagnesaemic by dietary deprivation of Mg 2+.…”

Section: Discussionmentioning

confidence: 52%

Magnesium deficiency increases ketamine sensitivity in rats

et al. 1997

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Magnesium deficiency increases ketamine sensitivity in ratsPurpose: Inhibition of the NMDA receptor likely contributes to ketamine's neurodepressive properties, Magnesium also inhibits the NMDA receptor by binding to a site associated with the ketamine-binding domain. Electrophysiological studies suggest that magnesium prevents ketamine from binding to the NMDA receptor and thereby prevents ketarnine inhibition. We undertook an in v/vo study to determine if magnesium defK:iency was associated with an increased sensitivity to ketamine. Methods: Weanling rats were maintained on a Ng2+-deficient or control diet for 14 days, In Study I, rats were anaesthetized then sacrificed and the Mg 2+ concentrations in the brain and plasma were measured. In a second prospective study, experimental animals were rendered hypomagnesaernic and the potency of 125 rng.kg -~/p ketamine was evaluated. Animals were then were fed a Mg 2 § diet and ketarnine sensitivity was re-examined 14 days later. R~ults: The Mg2 § diets rendered the rats hypornagnesaemic as indicated by the brain and plasma concentration of Mg 2+, In Study 2, the time to loss of fighting reflex was shorter: 1.9 4-0.3 rnin (n = 12) and 2.6 4-0.2 rnin (n = 16, P < 0.05), whereas the latency to toe pinch was prolonged: 25.0 -5.8 rnin (n= 12) vs 3. I +-2. I rnin (n = 16, P < 0.05) in the Mg2+-delicient compared with age-matched control animals, respectively. The hypornagnesaemic animals had a higher death rate following ketamine injec'don. The increased sensitivity to ketamine was no longer apparent when the animals were re-tested following replenishment of Mg 2+. Conclusion: Hypornagnesaemia is associated with an increased sensitivity to ketamine.

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“…These 1000× stock solutions were then diluted in Optimem (Gibco BRL, Gaithersburg, MD) to create media containing 5−60 uM memantine. This concentration range exceeds serum levels of memantine obtained with human usage (0.5−1.0 uM), but is in accordance with the concentration spectrum typically used for in vitro studies [17,18,19]. To accomplish APV exposures, APV (formula weight 203.1; Sigma, St. Louis) was dissolved in sterile water to generate a 1000×, 50 mM stock solution.…”

Section: Cell Culturementioning

confidence: 55%

Effects of memantine on mitochondrial function

McAllister

Ghosh

Berry

et al. 2008

Biochemical Pharmacology

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Because NMDA complex and mitochondrial function are related, we hypothesized memantine would influence mitochondrial function. We addressed this in vitro by studying the effects of chronic and acute memantine exposures on mitochondrial function. For acute exposure experiments, mitochondria were isolated from NT2 cells and assayed for electron transport chain (ETC) enzyme function and peroxide production in buffers containing up to 60 uM memantine. For chronic exposure experiments, NT2 cells were maintained for at least two weeks in medium containing up to 60 uM memantine, following which we assayed cells or their mitochondria for ETC enzyme activities, cytochrome oxidase protein levels, oxidative stress, calcium levels, and mitochondrial DNA levels. The ability of the NMDA receptor antagonist aminophosphonovaleric acid (APV) to modify memantine's mitochondrial effects was evaluated. Acute and chronic memantine similarly affected complex I (increased at high concentrations) and IV (decreased at high concentrations) Vmax activities. APV did not alter the effects of chronic memantine exposure on citrate synthase and complex IV. We detected a lower mitochondrial peroxide production rate with acute exposure, and an increased mitochondrial peroxide production rate with chronic exposure. Micromolar memantine concentrations affect mitochondria, some of these effects are directly mediated, and acute and chronic effects may differ.

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Comparison of the potency, kinetics and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo

Cited by 280 publications

References 42 publications

Amantadine Inhibits NMDA Receptors by Accelerating Channel Closure during Channel Block

Amantadine Inhibits NMDA Receptors by Accelerating Channel Closure during Channel Block

Magnesium deficiency increases ketamine sensitivity in rats

Effects of memantine on mitochondrial function

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