Nasal Administration of bFGF-Loaded Nanoliposomes Attenuates Neuronal Injury and Cognitive Deficits in Mice with Vascular Dementia Induced by Repeated Cerebral Ischemia‒Reperfusion

Int J Nanomedicine. 2024 Feb 12:19:1431-1450. doi: 10.2147/IJN.S452045. eCollection 2024.

Abstract

Introduction: Basic fibroblast growth factor (bFGF) shows great potential for preventing vascular dementia (VD). However, the blood‒brain barrier (BBB) and low bioavailability of bFGF in vivo limit its application. The present study investigated how nasal administration of bFGF-loaded nanoliposomes (bFGF-lips) affects the impaired learning and cognitive function of VD mice and the underlying mechanism involved.

Methods: A mouse model of VD was established through repeated cerebral ischemia‒reperfusion. A Morris water maze (MWM) and novel object recognition (NOR) tests were performed to assess the learning and cognitive function of the mice. Hematoxylin and eosin (HE) staining, Nissl staining and TUNEL staining were used to evaluate histopathological changes in mice in each group. ELISA and Western blot analysis were used to investigate the molecular mechanism by which bFGF-lips improve VD incidence.

Results: Behavioral and histopathological analyses showed that cognitive function was significantly improved in the bFGF-lips group compared to the VD and bFGF groups; in addition, abnormalities and the apoptosis indices of hippocampal neurons were significantly decreased. ELISA and Western blot analysis revealed that bFGF-lips nasal administration significantly increased the concentrations of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), bFGF, B-cell lymphoma 2 (Bcl-2), phosphorylated protein kinase B (PAKT), nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H quinone oxidoreductase 1 (NQO1) and haem oxygenase-1 (HO-1) in the hippocampus of bFGF-lips mice compared with the VD and bFGF groups. Furthermore, the concentrations of malondialdehyde (MDA), caspase-3 and B-cell lymphoma 2-associated X (Bax) were clearly lower in the bFGF-lips group than in the VD and bFGF groups.

Conclusion: This study confirmed that the nasal administration of bFGF-lips significantly increased bFGF concentrations in the hippocampi of VD mice. bFGF-lips treatment reduced repeated I/R-induced neuronal apoptosis by regulating apoptosis-related protein concentrations and activating the phosphatidylinositol-3-kinase (PI3K)/(AKT)/Nrf2 signaling pathway to inhibit oxidative stress.

Keywords: bFGF; nanoliposomes; nasal administration; neuronal apoptosis; oxidative stress; vascular dementia.

MeSH terms

  • Administration, Intranasal
  • Animals
  • Apoptosis
  • Brain Ischemia* / drug therapy
  • Cerebral Infarction
  • Cognition
  • Dementia, Vascular* / drug therapy
  • Dementia, Vascular* / metabolism
  • Dementia, Vascular* / pathology
  • Fibroblast Growth Factor 2 / metabolism
  • Mice
  • NF-E2-Related Factor 2 / metabolism
  • Neurons / metabolism
  • Oxidative Stress
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Reperfusion

Substances

  • Fibroblast Growth Factor 2
  • NF-E2-Related Factor 2
  • Proto-Oncogene Proteins c-bcl-2

Grants and funding

This research was supported by Zhejiang Provincial Medical And Health Science And Technology Project (Grant No. 2021KY1068, 2021KY1067), Ningbo Natural Science Foundation (Grant No. 202003N4337, 202003N4295), Yinzhou District Science And Technology Project (Grant No. 2019AS0021, Grant No. Yinke 202045).