Propofol treatment modulates neurite extension regulated by immunologically challenged rat primary astrocytes: a possible role of PAI-1
- 418 Downloads
Propofol, a widely used anesthetic, regulates neurological processes including neurotoxicity, neuroprotection, glial activation, synaptic plasticity and neuronal maturation. Tissue plasminogen activator/tissue plasminogen activator inhibitor-1 (tPA/PAI-1) in CNS acts as a neuromodulator regulating synaptic plasticity, neurite outgrowth, seizure spreading and cell survival. Here, we investigated the effects of propofol on tPA/PAI-1 system using cultured neurons and astrocytes and their role in the regulation of neurite extension. Cultured rat primary astrocytes were treated with propofol (1–10 µM) and LPS (10 ng/ml). The expression of functional tPA/PAI-1 was examined by casein zymography, Western blot and RT-PCR. Alternatively, culture supernatants were added to cultured rat primary neuron to investigate the effects on neurite extension. Propofol alone did not affect tPA activity in rat primary cortical neuron. Similarly, propofol alone changed neither tPA nor PAI-1 activity in rat primary astrocytes. In immunologically challenged situation using LPS, propofol synergistically increased expression of PAI-1 in rat primary astrocytes without affecting tPA expression in a manner dependent on MAPKs activation. Increased expression of PAI-1 reduced tPA activity in LPS plus propofol-treated rat primary astrocytes. Consistent with the critical role of tPA activity in the regulation of neurite extension (Cho et al. 2013), the diminished tPA activity in astrocyte culture supernatants resulted in decreased neurite extension when administered to cultured rat primary cortical neuron. The results from the present study suggest that propofol, especially in immunologically-challenged situation, dysregulates tPA/PAI-1 system in brain. Whether the dysregulated tPA/PAI-1 activity adversely affects neural differentiation as well as regeneration of neuron in vivo should be empirically determined in the future.
KeywordsPropofol tPA PAI-1 Neurite extension
This work was supported by a grant of the Korean Health Technology R&D Project, Ministry of health & welfare, Republic of Korea (No. A120029) and was also supported in part by the Faculty Research assistance Program of Yonsei University College of Medicine for 2013 (6-2013-0145).
Conflict of interest
The authors declare that they have no conflict of interests.
- Briner, A., I. Nikonenko, M. De Roo, A. Dayer, D. Muller, and L. Vutskits. 2011. Developmental stage-dependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex. Anesthesiology 115(2): 282–293. doi: 10.1097/ALN.0b013e318221fbbd.CrossRefPubMedGoogle Scholar
- Dennler, S., S. Itoh, D. Vivien, P. ten Dijke, S. Huet, and J.M. Gauthier. 1998. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. The EMBO Journal 17(11): 3091–3100. doi: 10.1093/emboj/17.11.3091.CrossRefPubMedCentralPubMedGoogle Scholar
- Docagne, F., O. Nicole, H.H. Marti, E.T. MacKenzie, A. Buisson, and D. Vivien. 1999. Transforming growth factor-beta1 as a regulator of the serpins/t-PA axis in cerebral ischemia. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology 13(11): 1315–1324.Google Scholar
- Gabriel, C., C. Ali, S. Lesne, et al. 2003. Transforming growth factor alpha-induced expression of type 1 plasminogen activator inhibitor in astrocytes rescues neurons from excitotoxicity. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology 17(2): 277–279. doi: 10.1096/fj.02-0403fje.Google Scholar
- Gorina, R., M. Font-Nieves, L. Marquez-Kisinousky, T. Santalucia, and A.M. Planas. 2011. Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFkappaB signaling, MAPK, and Jak1/Stat1 pathways. Glia 59(2): 242–255. doi: 10.1002/glia.21094.CrossRefPubMedGoogle Scholar
- Kim, J.W., S.H. Lee, H.M. Ko, et al. 2011. Biphasic regulation of tissue plasminogen activator activity in ischemic rat brain and in cultured neural cells: essential role of astrocyte-derived plasminogen activator inhibitor-1. Neurochemistry International 58(3): 423–433. doi: 10.1016/j.neuint.2010.12.020.CrossRefPubMedGoogle Scholar