The Concentration of Memantine in the Cerebrospinal Fluid of Alzheimer’s Disease Patients and Its Consequence to Oxidative Stress Biomarkers

Abstract

Memantine is a noncompetitive N -methyl-d-aspartate (NMDA) receptor antagonist utilized as a palliative cure for Alzheimer’s disease. This is the second study examining the memantine concentrations in cerebrospinal fluid. The previously published study enrolled six patients, and three of them were theoretically in a steady state. In our study, we enrolled 22 patients who regularly used a standard therapeutic dose of memantine (20 mg/day, oral administration) before the sample collection. Patients were divided into four groups, according to the time of plasma and cerebrospinal fluid collection: 6, 12, 18, and 24 h after memantine administration. The cerebrospinal fluid samples were also assessed for selected oxidative stress parameters (malondialdehyde, 3-nitrotyrosine, glutathione, non-protein thiols, and non-protein disulfides). The plasma/cerebrospinal fluid (CSF) ratio for all time intervals were within the range of 45.89% (6 h) to 55.60% (18 h), which corresponds with previously published findings in most patients. The other aim of our study was to deduce whether the achieved “real” memantine concentration in the central compartment was sufficient to block NMDA receptors. The IC 50 value of memantine as an NMDA antagonist is in micromolar range; the lowest limit is 112 ng/ml (GluN2C), and this value was achieved only in three cases. The memantine cerebrospinal fluid concentration did not reach one quarter of the IC 50 value in five cases (one patient was excluded for noncompliance); therefore, the potency of memantine as a therapeutic effect in patients may be questionable. However, it appears that memantine therapy positively affected the levels of some oxidative stress parameters, especially non-protein thiols and 3-nitrotyrosine.

Memantine and Its Combination with Acetylcholinesterase Inhibitors in Pharmacological Pretreatment of Soman Poisoning in Mice

“…Of note, memantine reduces OP-induced cell death in various vulnerable brain regions such as the amygdala, thalamus, piriform cortex, hippocampus, and parietal cortex (Jackson et al 2019). Moreover, memantine lowers levels of oxidative stress markers in the cerebrospinal fluid, especially non-protein thiols and 3-nitrotyrosine (Valis et al 2019). Although we used the maximal recommended dose (20 mg/kg; Stojiljkovic et al 2019), memantine alone as pretreatment decreased the toxicity of soman only slightly (the protective ratio 1.18) and grants little to no effect in the efficacy of post-exposure treatment (see Tables 2 and 3).…”

The Role of Oxidative Stress in Physiopathology and Pharmacological Treatment with Pro- and Antioxidant Properties in Chronic Diseases

“…Memantine decreases levels of advanced protein oxidation products (AOPP) and advanced glycation end products (AGEs) in patients with prediabetes and cognitive impairment [ 149 ]. In addition, memantine can decrease nitrosative stress and increase antioxidant protection of nonprotein thiols in the cerebrospinal fluid [ 150 ].…”

Anti-Amnesic and Neuroprotective Effects of Fluoroethylnormemantine in a Pharmacological Mouse Model of Alzheimer’s Disease

“…The reason why this effect does not translate in patients remains to be understood, but it is worth noting that the proposed Memantine (Ebixa) AD treatment is 20 mg/d, which corresponds to a lower dose than those used in preclinical neuroprotection studies. Recent results indicated that Memantine levels in the cerebrospinal fluid during memantine treatment are not sufficient to trigger NMDA response ( Valis et al, 2019 ).…”