| First Author | Tran TV | Year | 2018 |
| Journal | Mol Neurobiol | Volume | 55 |
| Issue | 5 | Pages | 4136-4159 |
| PubMed ID | 28597397 | Mgi Jnum | J:315594 |
| Mgi Id | MGI:6829338 | Doi | 10.1007/s12035-017-0638-8 |
| Citation | Tran TV, et al. (2018) Protein Kinase Cdelta Gene Depletion Protects Against Methamphetamine-Induced Impairments in Recognition Memory and ERK1/2 Signaling via Upregulation of Glutathione Peroxidase-1 Gene. Mol Neurobiol 55(5):4136-4159 |
| abstractText | Accumulating evidence has suggested that repeated treatment with methamphetamine (MA) resulted in cognitive impairments. Importantly, we show that selective upregulation of protein kinase Cdelta (PKCdelta) in the prefrontal cortex (PFC) of wild-type mice persisted for 28 days post withdrawal of MA. On day 28, the MA-induced increase in phospho-PKCdelta expression and decrease in phospho-ERK1/2 expression were significantly attenuated by both the Src inhibitor PP2 and the dopamine D1 receptor antagonist SCH 23390. However, neither protein kinase A inhibitor H89 nor calmodulin-dependent protein kinase II inhibitor KN93 attenuated MA-induced alterations in phospho-PKCdelta expression and phospho-ERK1/2 expression. Since PKCdelta knockout (KO) significantly increased the expression of glutathione peroxidase (GPx)-1, we also utilized GPx-1 KO and GPx-1-overexpressing transgenic (GPx-1 TG) mice. Repeated MA treatment induced cognitive impairment, as assessed by the novel object recognition test. Moreover, the extent of cognitive impairment correlated with the extent of increased phospho-PKCdelta expression and decreased GPx1 expression. In the absence of MA, exposure to novel objects increased phospho-ERK1/2 and GPx-1 expression in the PFC; however, these expression levels were decreased in the presence of MA. PKCdelta KO and GPx-1 TG mice each exhibited significantly attenuated MA-induced decreases in phospho-ERK1/2 and GPx-1 expression. Consistently, PKCdelta inhibition induces GPx/GSH-dependent antioxidant systems. More importantly, the antipsychotic drug clozapine significantly protected against cognitive impairment and was associated with alterations in phospho-ERK1/2 and phospho-PKCdelta expression. However, GPx-1 KO potentiated MA-induced cognitive deficits and alterations in phospho-ERK1/2 and phospho-PKCdelta expression. These results suggest that MA induces cognitive impairment by inhibiting ERK1/2 signaling, activating PKCdelta, and inactivating GPx-1 by upregulating Src kinase or the D1 receptor. They also suggest that clozapine requires activation of ERK1/2 signaling via positive modulation between the phospho-PKCdelta and GPx-1 genes to restore cognitive function. |
