Neuroprotection by N-methyl-d-aspartate antagonists in focal cerebral ischemia is dependent on continued maintenance dosing

Dextromethorphan as a Potential Neuroprotective Agent With Unique Mechanisms of Action

“…89 However, continuous perfusion of DM up to 4 hours after ischemic insult was shown to be necessary for maximum efficacy against focal ischemic damage. 42 This finding, and the use of multiple dose treatment paradigms in focal ischemia models, 45,49 also suggest a DM neuroprotective effect on delayed neuronal damage.…”

“…27 However, attempts to attribute neuroprotective activity of DM purely to NMDA receptor/channel antagonism are complicated by its relatively low-affinity for that complex, 1,2 as well as by inconsistent findings regarding its ability to prevent glutamate neurotoxicity. 25 Moreover, DM has been shown to have a broader spectrum of neuroprotective effects compared with other NMDA receptor/channel antagonists, 89 with a longer therapeutic time window in focal ischemia 42 and an ability to inhibit delayed neuronal death in global ischemia. 41 It is therefore apparent that mechanisms that may include but are not limited to NMDA receptor/channel antagonism contribute to DM's neuroprotective actions.…”

“…49 In a rabbit focal ischemia model, a 20 mg/kg (IV) loading dose alone was not neuroprotective, unless given with a 10 mg/kg/h maintenance infusion. 42 The single clinical study wherein neuroprotective effects were observed used DM oral doses between 36 to 38 mg/kg/d (concentrations of about 550 -1650 ng/mL maximum in plasma and 285-939 ng/mL in CSF). 71 In the other 3 clinical neuroprotection trials, oral doses of only 1.5 to 6 mg/kg/d were employed, which are about 10-to 20-fold below known neuroprotective doses.…”

Influence of the antioxidants vitamin E and idebenone on retinal cell injury mediated by chemical ischemia, hypoglycemia, or oxidative stress

“…MK-801 failed to reduce retinal cell damage under our experimental conditions, despite used at low concentrations to allow specific interactions with the NMDA receptor, maintained during all the experiment and under conditions that induced the opening of the receptor associated channel, in experiments carried out in the absence of Mg 2ϩ (not shown). Nevertheless, Steinberg et al [35] showed previously that MK-801 could be effective as a neuroprotector against focal cerebral ischemia if the dose applied was maintained. Earley et al [36] also showed neuroprotective effects of MK-801 against cortical damage induced by cerebral ischemia and, in the retina, Zeevalk and Nicklas [37,38] found protective effects of MK-801 (1 M) against toxicity induced by 30 min-metabolic inhibition.…”

Insulin-dependent diabetes mellitus induced by the antitussive agent dextromethorphan

“…Our finding of lower prevalence of susceptible heterodimers in adult-onset than in childhood-onset Type I diabetes could suggest either the involvement of other loci in the genetic susceptibility of the disease in adults or heterogeneity of environmental determinants by age at onset of the disease. Insulin-dependent diabetes mellitus induced by the antitussive agent dextromethorphan Dear Sir, In animal studies, antagonists of the N-methyl-d-aspartate (NMDA) receptor, which is a subtype of ionotropic glutamate receptors, are neuroprotective in focal cerebral ischaemia and therefore became a hot topic in brain research [1,2]. Dextromethorphan, a widely used antitussive agent, has non-competitive antagonistic effects at the NMDA receptor [3].…”