Reversible Changes in BDNF Expression in MK-801-Induced Hippocampal Astrocytes Through NMDAR/PI3K/ERK Signaling

Abstract

Dizocilpine (MK-801), a non-competitive N-methyl-D-aspartic acid receptor (NMDA-R) antagonist, can induce schizophrenia-like symptoms in healthy individuals, implicating NMDA-R hypofunction in disease pathogenesis. Brain-derived neurotrophic factor (BDNF) is also implicated in schizophrenia, and expression is regulated by NMDA-R activity, suggesting a functional link. We previously found that BDNF signaling was upregulated by MK-801 in cultured hippocampal astrocytes, but the underlying mechanism is not clear. To address this issue, the levels of BDNF expression and secretion were evaluated in hippocampal astrocytes incubated with MK-801 by ELISA and qPCR, with and without NMDA co-incubation or pretreatment of either the ERK1/2 inhibitor, PD98059 or the PI3K inhibitor, LY294002. The apoptosis, viability, and proliferation of the astrocytes were also examined. In the current study, we demonstrate that MK-801 treatment (20 μM for 5 days) enhances the proliferation of rat cultured hippocampal astrocytes. Expression of BDNF mRNA was enhanced after 24 h in MK-801, but returned to near baseline over the next 24 h in the continued presence of MK-801. However, two successive 24-h treatments enhanced BDNF expression. These application regimens had no effect on apoptosis or proliferation rate. Co-addition of NMDA significantly inhibited MK-801-induced upregulation of BDNF. Similarly, MK-801-induced BDNF upregulation was blocked by pretreatment with inhibitors of PI3K and ERK1/2, but not by inhibitors of p38 and JNK. These findings suggested that astrocytes may contribute to the acute neurological and behavioral response to MK-801 treatment via a transient increase in BDNF expression involving NMDA-R–PI3K–ERK signaling.

Decreased Brain pH and Pathophysiology in Schizophrenia

“…One might expect that the plasma membrane expression of NHE5 should be low in schizophrenia with hypofunction of NMDA receptors and BDNF levels should be elevated. There are clinical and experimental reports that ketamine or MK-801 elevates BDNF and TrkB levels [120][121][122]. However, the elevation was transient and did not last.…”

Advantages and Limitations of Animal Schizophrenia Models

“…However, previous studies have shown rather contrary results in terms of the BDNF levels after MK-801 treatment. Regarding the role of BDNF in memory/learning processes, MK-801 is expected to diminish the BDNF levels, and in some studies, it does, mainly in the hippocampus [ 127 , 128 ], but other studies have reported upregulated levels, including in vitro studies [ 129 , 130 ], which may suggest a response to the toxic action of MK-801 and/or action of compensatory mechanisms.…”

Avaliação da associação de canabidiol e nitroprussiato de sódio no prejuízo sensório-motor induzido pelo tratamento agudo com MK-801

“…Ensaios biológicos usando animais ou culturas celulares como modelos ainda estão surgindo, com o objetivo de fornecer mais informações sobre os efeitos induzidos pela administração de neuromoduladores e drogas antipsicóticas (GÜNERI; SCHEEL-KRÜGER; LUO, 2021; PEREZ-RANDO et al, 2017;WANG et al, 2019;YU et al, 2021).…”

“…O composto MK-801 possui uma afinidade, seletividade e potência inibitória maior do que a cetamina e a fenciclidina (WALLACH et al, 2016;YU et al, 2015), portanto, esse composto é amplamente empregado em modelos animais para induzir alterações comportamentais e neuroquímicas relacionadas à esquizofrenia. Ele pertence à classe das aminas secundárias e atua como antagonista não competitivo de receptor NMDA, não apenas em neurônios, mas também em células da glia (BRANDÃO-TELES et al, 2017;YU et al, 2015YU et al, , 2021. Em roedores, nos efeitos comportamentais induzidos pelo MK-801 estão incluídos prejuízo no aprendizado espacial e na memória (SAWAHATA et al, 2021;XIAO et al, 2019), sociabilidade reduzida (BIAŁOŃ et al, 2021;PERDIKARIS;DERMON, 2022;XIAO et al, 2019), hipolocomoção (SANTILLÁN-URQUIZA et al, 2019) ou hiperlocomoção (KRAEUTER et al, 2020;XIAO et al, 2019) e perturbações de condicionamento de medo (BIAŁOŃ et al, 2021;ZHAN et al, 2021) 2015).…”