Dizocilpine: Difference between revisions

As an antidepressant, positive results were found in [[animal models of depression]].<ref>{{cite journal |author=Berk M |title=Depression therapy: future prospects |journal=Int J Psychiatry Clin Pract |volume=4 |issue=4 |pages=281–6 |year=2000 |doi=10.1080/13651500050517830|pmid=24926578 |s2cid=41078092 }}</ref> NMDA antagonists like dizocilpine have been shown in animal models to attenuate the hearing loss caused by [[aminoglycosides]] It is thought that aminoglycosides mimic endogenous [[polyamine]]s at NMDA receptors and produce excitotoxic damage, leading to hair cell loss. Antagonizing NMDA receptors to reduce the excitotoxicity would prevent that hearing loss.<ref>{{cite journal |vauthors=Basile AS, Huang JM, Xie C, Webster D, Berlin C, Skolnick P |title=N-methyl-D-aspartate antagonists limit aminoglycoside antibiotic-induced hearing loss |journal=Nat. Med. |volume=2 |issue=12 |pages=1338–43 |date=December 1996 |pmid=8946832 |doi=10.1038/nm1296-1338 |s2cid=30861122 }}</ref><ref>{{cite journal |vauthors=Ernfors P, Canlon B |title=Aminoglycoside excitement silences hearing |journal=Nat. Med. |volume=2 |issue=12 |pages=1313–4 |date=December 1996 |pmid=8946827 |doi=10.1038/nm1296-1313 |s2cid=39020295 }} (Editorial)</ref> Dizocilpine was found to block the development of kindled [[seizure]]s, although it does not have any effect on completed kindled seizures.<ref>{{cite journal |vauthors=Post RM, Silberstein SD |title=Shared mechanisms in affective illness, epilepsy, and migraine |journal=Neurology |volume=44 |issue=10 Suppl 7 |pages=S37–47 |date=October 1994 |pmid=7969945 }}</ref> Oddly, it was discovered to decrease [[rabies]] virus production and is believed to be the first neurotransmitter antagonist to present with antiviral activity. Rat cortical neuron cells were infected with the rabies virus and those incubated with dizocilpine had virus produced reduced about 1000-fold. It is not known how MK-801 has this effect; the rabies virus suspension, without cells, was inoculated with dizocilpine and the drug failed to produce a virucidal effect, indicated that the mechanism of action is something other than direct discontinuation of virus reproduction. It was also tested against herpes simplex, vesicular stomatitis, poliovirus type I, and [[https://en.wikipedia.org/wiki/HIV|human immunodeficiency virus]]. It did not have activity against these other viruses, however.<ref>{{cite journal |vauthors=Tsiang H, Ceccaldi PE, Ermine A, Lockhart B, Guillemer S |title=Inhibition of rabies virus infection in cultured rat cortical neurons by an N-methyl-D-aspartate noncompetitive antagonist, MK-801 |journal=Antimicrob. Agents Chemother. |volume=35 |issue=3 |pages=572–4 |date=March 1991 |pmid=1674849 |pmc=245052 |doi=10.1128/AAC.35.3.572}}</ref> Dizocilpine was also shown to potentiate the ability of [[levodopa]] to ameliorate [[akinesia]] and muscular rigidity in a rodent model of [[parkinsonism]].<ref>{{cite journal |vauthors=Klockgether T, Turski L |title=NMDA antagonists potentiate antiparkinsonian actions of L-dopa in monoamine-depleted rats |journal=Ann. Neurol. |volume=28 |issue=4 |pages=539–46 |date=October 1990 |pmid=2252365 |doi=10.1002/ana.410280411 |s2cid=12624754 }}</ref> When dizocilpine was administered to rats 15 minutes after a spinal trauma, the long-term neurological recovery of the trauma was improved.<ref>{{cite journal |vauthors=Faden AI, Lemke M, Simon RP, Noble LJ |title=N-methyl-D-aspartate antagonist MK801 improves outcome following traumatic spinal cord injury in rats: behavioral, anatomic, and neurochemical studies |journal=J. Neurotrauma |volume=5 |issue=1 |pages=33–45 |year=1988 |pmid=3057216 |doi=10.1089/neu.1988.5.33 }}</ref> However, NMDA antagonists like dizocilpine have largely failed to show safety in [[clinical trial]]s, possibly due to inhibition of NMDA receptor function that is necessary for normal [[neuron]]al function. Since dizocilpine is a particularly strong NMDA receptor antagonist, this drug is particularly likely to have [[psychotomimetic]] side effects (such as [[hallucination]]s) that result from NMDA receptor blockade. Dizocilpine had a promising future as a neuroprotective agent until neurotoxic-like effects, called [[Olney's Lesions]], were seen in certain [[brain]] regions of lab rats.<ref name="Olney89">{{cite journal |vauthors=Olney JW, Labruyere J, Price MT |title=Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs |journal=Science |volume=244 |issue=4910 |pages=1360–2 |date=June 1989 |pmid=2660263 |doi=10.1126/science.2660263|bibcode=1989Sci...244.1360O }}</ref><ref name="ellison">{{cite journal |author=Ellison G |title=The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias |journal=Brain Res. Brain Res. Rev. |volume=20 |issue=2 |pages=250–67 |date=February 1995 |pmid=7795658 |doi=10.1016/0165-0173(94)00014-G|s2cid=24071513 }}</ref> [[Merck & Co.|Merck]], a drug company, promptly dropped development of dizocilpine.