Intranasal delivery of berberine via in situ thermoresponsive hydrogels with non-invasive therapy exhibits better antidepressant-like effects

The efficacy of antidepressant therapy is frequently limited by challenges related to the potential to reach the brain. The development of new strategies to deliver more antidepressants to the brain so as to bypass the blood-brain barrier (BBB) is beneficial for the treatment of nervous system diseases, especially depression. Here, we have reported an unconventional strategy by the intranasal delivery of berberine with an in situ thermoresponsive hydrogel as the holder in the nasal cavity to improve its antidepressant-like activity. A berberine/hydroxylpropyl-beta-cyclodextrin (HP-beta-CD) inclusion complex was first prepared to improve the solubility of berberine and loaded into a thermoresponsive hydrogel system of poloxamers. A radioactive tracer of I-125-labeled berberine was used to investigate brain targeting. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed to study the pharmacokinetic change in the hippocampus. Monoamine neurotransmitters were analyzed in a reserpine-induced depression model, and metabolomic analysis of the hippocampus was performed in a chronic unpredictable mild stress (CUMS)-induced depression model. The radioactive tracer analysis manifested that the thermoresponsive hydrogel administered intranasally could maintain a high concentration gradient of berberine to the brain, and the relative bioavailability of berberine was enhanced approximately by 110 times that of the oral berberine/HP-beta-CD inclusion complex in the hippocampus. The thermoresponsive hydrogel system resulted in similar or better antidepressant-like efficacy even with a lower dosage in reserpine and CUMS-induced depression in rats. The pharmacometabolomics analysis revealed that in addition to increasing the hippocampal monoamine levels, berberine via intranasal administration exhibited a unique mechanism by restoring the mitochondrial dysfunction as well as phospholipid and sphingolipid abnormalities as compared to intragastric (IG) administration. We consider this a safer and more effective strategy with a lower dosage than traditional oral drugs for the treatment of depression.