Propofol treatment modulates neurite extension regulated by immunologically challenged rat primary astrocytes: a possible role of PAI-1

Abstract

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.