Memantine is protective against cytotoxicity caused by lead and quinolinic acid in cultured rat embryonic hippocampal cells

Abdur Rahman, Sara Al-Qenaie, Muddanna S. Rao, Khalid M. Khan, Gilles J. Guillemin

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Pages1134-1143
Number of pages10
JournalChemical Research in Toxicology
Volume32
Issue number6
Early online date5 Apr 2019
DOIs
Publication statusPublished - 17 Jun 2019

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Quinolinic Acid
Memantine
Cytotoxicity
Rats
Oxidative stress
N-Methyl-D-Aspartate Receptors
Astrocytes
Neurons
Cell Survival
Oxidative Stress
Cells
Apoptosis
Kynurenine
Lead
Flow cytometry
Propidium
Annexin A5
Glial Fibrillary Acidic Protein
Tubulin
Metabolites

Cite this

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title = "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.",
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Memantine is protective against cytotoxicity caused by lead and quinolinic acid in cultured rat embryonic hippocampal cells. / Rahman, Abdur; Al-Qenaie, Sara; Rao, Muddanna S.; Khan, Khalid M.; Guillemin, Gilles J.

In: Chemical Research in Toxicology, Vol. 32, No. 6, 17.06.2019, p. 1134-1143.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Memantine is protective against cytotoxicity caused by lead and quinolinic acid in cultured rat embryonic hippocampal cells

AU - Rahman, Abdur

AU - Al-Qenaie, Sara

AU - Rao, Muddanna S.

AU - Khan, Khalid M.

AU - Guillemin, Gilles J.

PY - 2019/6/17

Y1 - 2019/6/17

N2 - 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.

AB - 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.

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U2 - 10.1021/acs.chemrestox.8b00421

DO - 10.1021/acs.chemrestox.8b00421

M3 - Article

VL - 32

SP - 1134

EP - 1143

JO - Chemical Research in Toxicology

T2 - Chemical Research in Toxicology

JF - Chemical Research in Toxicology

SN - 0893-228X

IS - 6

ER -