Memantine Is Protective against Cytotoxicity Caused by Lead and Quinolinic Acid in Cultured Rat Embryonic Hippocampal Cells

Abstract

Quinolinic acid (QA) is an excitotoxic metabolite of the kynurenine pathway of tryptophan metabolism produced in response to inflammation and oxidative stress. Lead (Pb) causes oxidative stress and thus may produce neurotoxicity by increasing QA production. We investigated the in vitro cytotoxic effects of Pb and QA and the protective effects of the NMDA receptor antagonist memantine. Primary cultures of embryonic hippocampal cells from Wistar rats were treated with different concentrations of Pb, QA, and Pb + QA with and without memantine. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Apoptosis was analyzed by flow cytometry after Annexin-V/propidium iodide staining. The numbers of immunostained neurons (with β3-Tubulin; Tuj1) and astrocytes (with glial fibrillary acidic protein) were counted. Pb at 20 μg/dL (0.97 μM) and QA at 500 nM concentrations showed significant cytotoxic effects, as evidenced by decreased cell viability, increased apoptosis, and a decrease in the number of both astrocytes and neurons. The combination of Pb and QA showed significant synergistic apoptotic effects at lower doses. Memantine (500 nM) was largely protective against the cytotoxic effects of both Pb and QA, suggesting that Pb’s and QA’s cytotoxicity involves NMDA receptor activation. Whereas the neuroprotection by memantine from QA-induced toxicity has been previously reported, this is the first study reporting the protection by memantine against Pb-induced cytotoxicity in cultured hippocampal cells. Protection by memantine against these neurotoxicants in vivo needs to be investigated.

Combining in vitro assays and mathematical modelling to study developmental neurotoxicity induced by chemical mixtures

“…An increase of GFAP + astrocytes was also demonstrated in NSCs derived from the hippocampus of newborn and adult rats treated with 0−200 μM Lead [ 124 ]. Contrary to our results, Lead treatment for 7d (0.97 μM, a concentration slightly higher than the ones tested in our study, i.e., 0.18−0.73 μM) was found to decrease the number of both astrocytes and neurons in primary cultures of embryonic rat hippocampal cells [ 125 ]. Altogether, these studies point to a dual role played by astrocytes upon Lead exposure: under specific conditions (e.g., low toxic concentrations and/or short exposure times), they may play a neuroprotective role; however, if their buffering capacity is compromised due to e.g., exposure to highly toxic concentrations and/or prolonged/chronic exposure, they may contribute to neuronal damage, a phenomenon accompanied also by release of inflammatory cytokines and chemokines [ 126 ].…”

SARS-CoV-2 infection in patients with serious mental illness and possible benefits of prophylaxis with Memantine and Amantadine

“…Oxidative stress and neuroinflammatory processes triggered by cytokine activation may have an excitotoxic effect through the action of quinolinic acid from tryptophan metabolism. The protective effect of Memantine has been demonstrated in hippocampal cell cultures from Wistar rats by reducing the apoptosis of neurons and astrocytes due to the antagonistic effect of NMDA receptors [ 164 ]. Memantine may have antiparkinsonian effects because it prevents the in vivo and in vitro death of brain neurons damaged by excitatory amino acids.…”

Astrocytes in heavy metal neurotoxicity and neurodegeneration

“…Humans are exposed to pathological load of metals through contaminated food, contaminated environment (water and air) or through occupational exposure Bai et al, 2019;Jan et al, 2015;Qu et al, 2012;Sarah et al, 2019); excess of metals in the body often results in neurotoxicity and associated neurological disorders. Excessive accumulation of metallic elements, such as arsenic (As), manganese (Mn), mercury (Hg), lead (Pb), aluminium (Al), nickel (Ni), bismuth (Bi), cadmium (Cd), zinc (Zn), copper (Cu) and iron (Fe), are known to be neurotoxic and - Viterbo et al,1977;Kirkley et al, 2017;Pamphlett and Kum, 2018;Rahman et al, 2019;Ijomone et al, 2020;Sudhakaran et al, 2019).…”