Olanzapine Ameliorates Ischemic Stroke-like Pathology in Gerbils and H2O2-Induced Neurotoxicity in SH-SY5Y Cells via Inhibiting the MAPK Signaling Pathway

Abstract

Olanzapine (OLNZ) is used to treat psychotic disorders. To look into the neurological basis of this phenomenon, we investigated the neuroprotective effects of OLNZ in gerbils and SH-SY5Y cells. Gerbils were subjected to transient global cerebral ischemia (TGCI) by blocking both common carotid arteries, and OLNZ (10 mg/kg) was injected intraperitoneally. Hydrogen peroxide (H2O2) was used to induce oxidative-stress-mediated damage in the SH-SY5Y cells. The results indicated that OLNZ administration markedly reduced neuron damage and glial cell triggering within CA1 zone of the hippocampus. We used RNA sequencing to assess the numbers of up-and downregulated genes involved in TGCI. We found that OLNZ treatment downregulated the expression of complement-component-related genes and the expression of mitogen-activated protein kinases (MAPKs) in the hippocampus. In cells, OLNZ co-treatment significantly improved cell viability and reduced lactate dehydrogenase (LDH), and reactive oxygen species (ROS) generation. Expression of antioxidant superoxide dismutase-1,2 enzymes (SOD-1, SOD-2) was also intensely upregulated by OLNZ, while the expression of MAPKs and NF-κB were reduced. Co-incubation with OLNZ also regulated apoptosis-related proteins Bax/Bcl-2 expression. Finally, the results demonstrated that treatment with OLNZ showed neuroprotective effects and that the MAPK pathway could involve in the protective effects.

Novel insight into the etiology of ischemic stroke gained by integrative multiome-wide association study

“…The mitogen-activated protein kinase (MAPK)-activated protein kinase 5 (APK5), a member of the serine/threonine kinase family, is activated by cellular stress and proinflammatory cytokines [ 35 ]. The MAPKAPK5 Antisense RNA 1 (MAPKAPK5-AS1) prevents MAPKAPK5 from being translated into a protein and recent study showed that IS-like pathology was ameliorated by inhibiting the MAPK signaling pathway [ 36 ]. Lastly, we performed PWAS fine-mapping to identify protein levels causally relevant to IS risk.…”

Identification of five characteristic ferroptosis-related genes as novel biomarkers for ischemic stroke using bioinformatic and machine learning strategies

“…Studies have shown that the MAPK signaling pathway is closely related to inflammation-mediated ischemic injury [24]. The MAPK signaling pathway inhibition can inhibit neuronal apoptosis and inflammatory response, protect damaged brain tissue, and improve nerve injury [25]. Many studies have also shown that PI3K/Akt signaling pathway is essential in the pathogenesis of ischemic stroke and plays a vital role in the anti-apoptosis of nerve cells, oxidative stress, inflammation, inflammation, and inflammation autophagy [26][27][28].…”

Novel insight into the etiology of ischemic stroke gained by integrative transcriptome-wide association study

“…The mitogen-activated protein kinase (MAPK)-activated protein kinase 5 (APK5), a member of the serine/threonine kinase family, is activated by cellular stress and proinflammatory cytokines [51]. The MAPKAPK5 Antisense RNA 1 (MAPKAPK5-AS1) prevents MAPKAPK5 from being translated into a protein and recent study showed that IS-like pathology was ameliorated by inhibiting the MAPK signaling pathway [52]. Lastly, we performed PWAS finemapping to identify protein levels causally relevant to IS risk.…”