Cancer-related
cognitive impairments (CRCI) are debilitating consequences of
cancer treatment with
platinum agents (e.g.,
cisplatin) that greatly alter cancer survivors' health-related quality of life.
Brain-derived neurotrophic factor (
BDNF) plays an essential role in neurogenesis, learning, and memory, and the reduction of
BDNF is associated with the development of
cognitive impairment in various
neurological disorders, including CRCI. Our previous CRCI rodent studies have shown that
cisplatin reduces hippocampal neurogenesis and
BDNF expression and increases hippocampal apoptosis, which is associated with
cognitive impairments. Few studies have reported on the effects of
chemotherapy and medical stress on serum
BDNF levels and cognition in middle-aged female rat models. The present study aimed to compare the effects of medical stress and
cisplatin on serum
BDNF levels and cognitive performance in 9-month-old female Sprague Dawley rats to age-matched controls. Serum
BDNF levels were collected longitudinally during
cisplatin treatment, and cognitive function was assessed by novel object recognition (NOR) 14 weeks post-
cisplatin initiation. Terminal
BDNF levels were collected ten weeks after
cisplatin completion. We also screened three
BDNF-augmenting compounds,
riluzole, ampakine
CX546, and CX1739, for their
neuroprotective effects on hippocampal neurons, in vitro . We assessed dendritic arborization by Sholl analysis and dendritic spine density by quantifying postsynaptic density-95 (PSD95) puncta.
Cisplatin and exposure to medical stress reduced serum
BDNF levels and impaired object discrimination in NOR compared to age-matched controls. Pharmacological
BDNF augmentation protected neurons against
cisplatin-induced reductions in dendritic branching and PSD95. Ampakines (
CX546 and CX1739) but not
riluzole altered the antitumor efficacy of
cisplatin in two human
ovarian cancer cell lines, OVCAR8 and SKOV3.ip1, in vitro. In conclusion, we established the first middle-aged rat model of
cisplatin-induced CRCI, assessing the contribution of medical stress and longitudinal changes in
BDNF levels with cognitive function. We conducted an in vitro screening of
BDNF-enhancing agents to evaluate their potential
neuroprotective effects against
cisplatin-induced neurotoxicity and their effect on
ovarian cancer cell viability.