Microdialysis is well established in chemical neuroscience as a mainstay technology for real time intracranial chemical monitoring in both animal models and human patients. Evidence shows that microdialysis can be enhanced by mitigating the penetration injury caused during the insertion of microdialysis probes into brain tissue. Herein, we show that retrodialysis of dexamethasone in the rat cortex enhances the microdialysis detection of K(+) and glucose transients induced by spreading depolarization. Without dexamethasone, quantification of glucose transients was unreliable by 5 days after probe insertion. With dexamethasone, robust K(+) and glucose transients were readily quantified at 2 h, 5 days, and 10 days after probe insertion. The amplitudes of the K(+) transients declined day-to-day following probe insertion, and the amplitudes of the glucose transients exhibited a decreasing trend that did not reach statistical significance. Immunohistochemistry and fluorescence microscopy confirm that dexamethasone is highly effective at preserving a healthy probe-brain interface for at least 10 days even though retrodialysis of dexamethasone ceased after 5 days.