Intranasal delivery of berberine via in situ thermoresponsive hydrogel with non-invasive therapy exhibits better antidepressant-like effects
The efficacy of antidepressant therapy is frequently limited by challenges of potential to reach the brain. The development of new strategies to deliver more antidepressant to brain bypass blood-brain barrier (BBB) is beneficial for the treatment of nervous system disease, especially for depression. Here, we report an unconventional strategy by intranasal delivery of berberine with in situ thermoresponsive hydrogel as holder in nasal cavity to improve its antidepressant-like activity. Berberine/HP-β-CD inclusion complex was firstly prepared to improve the solubility of berberine, and loaded into thermoresponsive hydrogel system of poloxamers. Radioactive tracer of 125I labeled berberine was used to investigate the brain targeting. LC-MS/MS analysis were performed to study the pharmacokinetic change in hippocampus. Monoamine neurotransmitters was analyzed in reserpine-induced depression model, and metabolomic analysis of hippocampus was performed in CUMS-induced depression model. The radioactive tracer analysis manifested that thermoresponsive hydrogel by intranasal administration could maintain a high concentration gradient of berberine to the brain, and the relative bioavailability of berberine was enhanced approximately 110 folds than oral berberine/HP-β-CD inclusion complex in the hippocampus. The thermoresponsive hydrogel system results in similar or better antidepressant-like efficacy even with the lower dosage in reserpine and chronic unpredicted mild stress-induced depressant-like rats. The pharmacometabolomic analysis revealed that in addition to increasing the hippocampal monoamines levels, berberine via intranasal administration exhibited the unique mechanism by restoring mitochondrial dysfunction, phospholipids and sphingolipids abnormalities than IG administration. We consider this as a safer and more effective strategy with a lower dosage than traditionally oral drugs for the treatment of depression.