Catalpol reverses doxorubicin-induced cognitive decline, neuroinflammation, and restores synaptic integrity

Cancer therapy-related cognitive impairments (CRCI) are detrimental for millions of cancer survivors. Chemotherapy induces neuroinflammation and reduces synaptic integrity, contributing to CRCI. Our past pre-clinical animal studies showed synaptic loss, including postsynaptic density protein 95 (PSD-95) and dynamin-1, that were associated with CRCI. Our human observational data showed reduced plasma dynamin-1 in breast cancer patients receiving chemotherapy. Since these proteins promote synaptic trafficking and plasticity that contribute to cognitive function, augmenting and protecting synaptic integrity represents a viable solution to reverse CRCI. Catalpol, a phytochemical, isolated from Rehmannia glutinosa (Gaertn.) Libosch. ex DC. plant root, has been shown to increase PSD-95 and dynamin-1, and reduce microglial activation in the injured brains.

This study tested the neuroprotective impact of oral catalpol treatment in the mouse model of CRCI.

Adult wild-type mice received either vehicle or chronic chemotherapy, doxorubicin (Adriamycin®, 3 mg/kg, intraperitoneal) once weekly for four weeks. 72 h after the last Adriamycin injection, mice were treated with catalpol (0.5 mg/ml corresponding to 50 mg/kg) for one month in drinking water (in addition to 50 mg/kg daily injections for the first 6 days), followed by cognitive function testing.

Administration of catalpol to Adriamycin-exposed mice significantly improved cognitive performance in the spatial recognition memory task. Hippocampal tissue analysis revealed that catalpol significantly reduced microglial activation and prevented loss of synaptic machinery proteins, including dynamin-1 and PSD-95, in the Adriamycin-exposed brains. Catalpol also restored hippocampal neurogenesis and neuronal plasticity-related cFos.

This data provides pre-clinical evidence of the feasibility of oral administration of catalpol as a phytopharmaceutical candidate for CRCI.