Intranasal bFGF‑Els alleviate doxorubicin‑induced cognitive deficits in mice by modulating the PI3K/AKT pathway and suppressing oxidative stress, neuroinflammation, and apoptosis.

Abstract

Chemotherapy-induced cognitive impairment (CICI), a frequent consequence of doxorubicin (DOX) treatment in patients with breast cancer, currently lacks effective preventive measures. This work explored whether administering basic fibroblast growth factor (bFGF)-encapsulated elastic nanoliposomes (bFGF-Els) administered intranasally could mitigate DOX-induced cognitive impairment in a mouse model of triple-negative breast cancer. The optimized bFGF-Els were spherical and uniform, with a mean size of 110.8  nm, a polydispersity index of 0.079, a zeta potential of -32.6  mV, an encapsulation efficiency of 87.5%, and favorable deformability. Compared with those receiving DOX alone, mice receiving intranasal bFGF-Els showed markedly better cognitive performance, as evidenced by reduced escape latency and increased platform crossing and target quadrant time (all P < 0.01). Histological and biochemical analyses revealed that bFGF-Els attenuated hippocampal CA1 neuronal damage, decreased reactive oxygen species and malondialdehyde levels, restored superoxide dismutase and glutathione peroxidase activity, and reduced pro‑inflammatory cytokines (interleukin‑1β, interleukin‑6, and tumor necrosis factor‑α) (all P < 0.01). At the mechanistic level, bFGF-Els increased the ratios of phosphorylated PI3K to total PI3K and phosphorylated AKT to total AKT and increased the levels of nuclear Nrf2 (nuclear factor erythroid 2‑related factor 2), heme oxygenase‑1(HO-1), NAD(P)H:quinone oxidoreductase‑1(NQO1), and B‑cell lymphoma 2 (Bcl-2), while reducing nuclear factor‑κB (NF-κB), Bcl‑2‑associated X protein (Bax), and cleaved caspase‑3 (all P < 0.01). bFGF-Els did not affect the anti-tumor efficacy of DOX, as the tumor volume and weight were similar among all the groups treated with DOX (P > 0.05). In conclusion, intranasal bFGF-Els enable efficient bFGF transport to the brain and relieves DOX-triggered CICI by curbing oxidative stress, neuroinflammation, and apoptosis through the PI3K/AKT axis, all while preserving the antitumor activity of chemotherapy.

Key Findings

• Intranasal administration of bFGF-encapsulated elastic nanoliposomes (bFGF-Els) improved cognitive performance in a doxorubicin (DOX)-induced mouse model of chemotherapy-induced cognitive impairment (CICI).
• bFGF-Els reduced hippocampal neuronal damage, decreased oxidative stress markers (ROS and MDA), restored antioxidant enzyme activities (SOD and GSH-Px), and lowered pro-inflammatory cytokines (IL-1β, IL-6, TNF-α).
• Mechanistically, bFGF-Els activated the PI3K/AKT pathway, increased nuclear Nrf2 and downstream antioxidant proteins (HO-1, NQO1), increased anti-apoptotic Bcl-2, and decreased NF-κB, pro-apoptotic Bax, and cleaved caspase-3 levels without affecting DOX’s anti-tumor efficacy.

Clinical Significance

Citation

Zhang Ming, He Wen-Yue, Ma Wei-Chenget al.. Intranasal bFGF‑Els alleviate doxorubicin‑induced cognitive deficits in mice by modulating the PI3K/AKT pathway and suppressing oxidative stress, neuroinflammation, and apoptosis. Brain, behavior, and immunity. 2026-Aug-28.