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Memantine Research Summary Explained – The Basics

Posted by Anonymous on August 01, 2015  /   Posted in Khemcorp Originals, Reverse Tolerance

Memantine Research Summary Explained – The Basics

What is Memantine?

Memantine is a novel unique drug that acts on the glutamatergic system by blocking NMDA Receptors, it is mainly prescribed for treating Alzheimer’s disease. Its effects for Alzheimer’s are actually questionable according to some studies, showing that has little use in mild Alzheimer’s, but reasonable results in moderate Alzheimers.

NMDA receptors are glutamate class receptors and ion channel protein found in nerve cells, activating it causes positive ions to flow through cell membranes. It is a critical part of controlling memory function, and also synaptic plasticity. Particularly calcium flux is one of the reasons drug tolerances happens (not the only mechanism, but a major one).

You will pretty much soon discover that Memantine maybe for some people a once in a lifetime chemical discovery. A strong emphasize on maybe given the evidence.

Memantine Nootropic, Tolerance Reversal, Autism and More

This hasn’t stopped scientists from discovering other ways Memantine can be used. It turns out that this is an extraordinary chemical. Interest in it increased when scientist found that Memantine causes a bunch of highly desirable effects, the most notable is its ability to reverse or block tolerance from other drugs, due the the aforementioned effect of being a non competitive NMDA receptor antagonist.

Clinically available NMDA receptor antagonists memantine and dextromethorphan reverse existing tolerance to the antinociceptive effects of morphine in mice.

In experiment 3, memantine and MRZ 2/579 (10 mg/kg) inhibited the acute antinociceptive effect of morphine, but dextromethorphan did not. These data indicate that low-affinity, clinically available and/or therapeutically promising NMDA receptor antagonists may be used to inhibit ongoing morphine tolerance.

Naunyn Schmiedebergs Arch Pharmacol. 2000 Apr;361(4):425-32.
Popik P1, Kozela E, Danysz W.
1Institute of Pharmacology, Polish Academy of Sciences, 

Memantine’s primary use is to decrease glutamate activity because too much glutamate activity causes cognitive impairment. On the other hand, too little is also not a good thing. This attribute means that for some people Memantine can act as a potent memory enhancer.

Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system

Parsons CG1, Stöffler A, Danysz W.

1Merz Pharmaceuticals, Eckenheimer Landstrasse 100, 60318 Frankfurt am Main, Germany.

Memantine also has research to suggest its use in the treatment of autism, and there is literally a cargo hold of studies proving it can block tolerance on a vast array of drugs.

Don’t get excited so quickly, though. Memantine definitely does not work as quickly as Proglumide, and it has quirky side effects which make dosing high impossible.

Oh did I also mention it also has neuroprotection against excitotoxicity?

Memantine’s Mechanism of Action – How It Works

Main Action (Glutamatergic NMDA Receptor)

Memantine causes massively increased Ca2+ evoked signals by inhibiting one of the main excitatory responses in the human brain. The brain responds compensate for the depleted Ca2+ by building more building more binding sites. This inhibition also stops the spiking or prolonged influx of Ca2+ ions, which gives it neuroprotective effects, as well as blocking tolerance to a degree. It also achieved this by blockading pre-synaptic CA2+ entry which we will return to, as this is its main proposed mechanism for reversing and blocking tolerance.

Secondary Actions

It doesn’t end there. Memantine then goes ahead and is also a non-competitive antagonist at the nicotinic acetylcholine receptors (nAChRs) just as strongly. It is also an antagonist at the serotonergic 5-HT3 Receptor. Some of this activity we will find later are troublesome.

Finally its also a agonist at the dopamine d2 receptor, which we will come back to because this means it is also of interest for people with social anxiety (often associated with the dysfunction of d2), or in ADHD where dopamine is function is impaired, it also induces d2 receptor synthesis in rats.

Chronic administration of NMDA antagonists induces D2 receptor synthesis in rat striatum.

These results suggest that the synthesis of both striatal D2 receptor isoforms is postsynaptically regulated at the transcriptional level, by events triggered by glutamate through the NMDA-type receptor.

Brain Res Mol Brain Res. 1992 Aug;14(4):363-8.
Micheletti G1, Lannes B, Haby C, Borrelli E, Kempf E, Warter JM, Zwiller J.
1Institut de Physiologie, Faculté de Médecine, Université Louis Pasteur, Strasbourg, France.

The Unique Traits that Make Memantine Truly Unique

What makes Memantine so special is that NMDA antagonists have been studied for a long time, in regards with their efficacies to the aforementioned problems above, but normal NMDA antagonists also costs a whole host of problems, as NMDA receptors are critical the function of the cognition system and synaptic plasticity, so most NMDA antagonist are deconstructive on memory capabilities e.g. Ketamine or DXM.

Memantine has a notable almost non-existent. the side effect profile. 

This is due to memantine being very voltage dependent, non-competitive, and also it only binds under certain conditions, importantly it unbinds upon depolarization of the neurone, coupled with its fast kinetics –

This means that memantine escapes from the ion channel quick enough, to allow normal functioning of the NMDA receptors, allowing passage of calcium and sodium ions critical to the operational circuitry of neuronal firing responsible for glutamine cognition.

This one attribute makes Memantine a one of a kind chemical, as it means it has all the advantages of an NDMA antagonist without the disadvantages of one.

This is part 1 on a series of research. Next Up: Research summary for Memantine as a tolerance reversal agent.

-Khemcorp

Research References:

Masui. 2009 Sep;58(9):1136-42.

[Anti-opioid action of glutamate-NMDA receptor systems underlying morphine analgesic tolerance].

[Article in Japanese]

Ueda H1, Matsushita Y.

Author information

  • 1Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523.

Neuropharmacology. 2007 Nov;53(6):699-723. Epub 2007 Aug 10.

Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system–too little activation is bad, too much is even worse.

Parsons CG1, Stöffler ADanysz W.

Author information

  • 1Merz Pharmaceuticals, Eckenheimer Landstrasse 100, 60318 Frankfurt am Main, Germany.

Brain Res Mol Brain Res. 1992 Aug;14(4):363-8.

Chronic administration of NMDA antagonists induces D2 receptor synthesis in rat striatum.

Micheletti G1, Lannes BHaby CBorrelli EKempf EWarter JMZwiller J.

Author information

  • 1Institut de Physiologie, Faculté de Médecine, Université Louis Pasteur, Strasbourg, France.

Psychopharmacology (Berl). 2008 Feb;196(3):497-509. Epub 2007 Nov 10.

NMDA receptor antagonists inhibit opiate antinociceptive tolerance and locomotor sensitization in rats.

Mendez IA1, Trujillo KA.

Neuropharmacology. 2008 Mar;54(3):588-96. doi: 10.1016/j.neuropharm.2007.11.013. Epub 2007 Nov 28.

The glycine site-specific NMDA antagonist (+)-HA966 enhances the effect of morphine and reverses morphine tolerance via a spinal mechanism.

Adam F1, Dufour ELe Bars D.

Author information

  • 1Institut National de la Santé et de la Recherche Médicale (INSERM) U-713, Université Pierre et Marie Curie, Faculté de Médecine Pitié-Salpêtrière, 91 Boulevard de l’Hôpital, 75013 Paris, Franc