Dolutegravir Inhibition of Matrix Metalloproteinases Affects Mouse Neurodevelopment.
Mol Neurobiol
; 58(11): 5703-5721, 2021 Nov.
Article
em En
| MEDLINE
| ID: mdl-34390469
ABSTRACT
Dolutegravir (DTG) is a first-line antiretroviral drug (ARV) used in combination therapy for the treatment of human immunodeficiency virus type-1 (HIV-1) infection. The drug is effective, safe, and well tolerated. Nonetheless, concerns have recently emerged for its usage in pregnant women or those of child-bearing age. Notably, DTG-based ARV regimens have been linked to birth defects seen as a consequence of periconceptional usages. To this end, uncovering an underlying mechanism for DTG-associated adverse fetal development outcomes has gained clinical and basic research interest. We now report that DTG inhibits matrix metalloproteinases (MMPs) activities that could affect fetal neurodevelopment. DTG is a broad-spectrum MMPs inhibitor and binds to Zn++ at the enzyme's catalytic domain. Studies performed in pregnant mice show that DTG readily reaches the fetal central nervous system during gestation and inhibits MMP activity. Postnatal screenings of brain health in mice pups identified neuroinflammation and neuronal impairment. These abnormalities persist as a consequence of in utero DTG exposure. We conclude that DTG inhibition of MMPs activities during gestation has the potential to affect prenatal and postnatal neurodevelopment.
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MEDLINE
Assunto principal:
Oxazinas
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Piperazinas
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Piridonas
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Antirretrovirais
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Inibidores de Metaloproteinases de Matriz
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Transtornos do Neurodesenvolvimento
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Doenças Neuroinflamatórias
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Compostos Heterocíclicos com 3 Anéis
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Defeitos do Tubo Neural
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article