Background: Chronic pain often results in cognitive impairment. Our previous study showed
that trigeminal neuralgia induced by cobra venom leads to spatial learning and memory deficits,
although the underlying mechanism remains unclear. However, recent evidence indicates that
the c-AMP-responsive element binding protein (CREB)/brain derived neurotrophic factor (BDNF)
pathway plays a critical role in various etiologies of cognitive deficits.
Objectives: Our aim was to explore the CREB/BDNF pathway to determine the molecular
mechanisms involved in the pathogenesis of cognitive impairment caused by cobra venominduced trigeminal neuralgia.
Study Design: A randomized, controlled animal study.
Setting: Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University.
Methods: Fifty male Sprague–Dawley rats were randomly divided into 3 groups: cobra venom
group, sham group, and control group. Cobra venom or saline was injected into the sheath of the
infraorbital nerve (ION), respectively. Video recordings and mechanical thresholds were used to
analyze changes in behavioral activity 3 days before surgery and 4, 7, 14, 21, 28, and 56 days after
surgery. Morris water maze tests were conducted at 4- and 8-week time points after surgery to
evaluate spatial learning and memory. We also investigated expression changes of phosphorylated
CREB (p-CREB) and BDNF in the hippocampus and prefrontal cortex (PFC) using western blotting
and immunohistochemistry.
Results: Cobra venom-treated rats exhibited significant changes in face grooming, as well as
exploratory and resting behaviors, compared with the control group and sham group (both P <
0.001). Rats in the cobra venom group exhibited slightly impaired acquisition (P < 0.05) without
memory deficits (P > 0.05) in the first water maze protocol. In the second water maze test, rats in
the cobra venom group exhibited spatial learning and memory deficits, with fewer platform site
crossings during the probe trial (P < 0.05). Moreover, results showed decreased p-CREB and BDNF
expressions in the hippocampus and PFC in the cobra venom group, with significant differences at
9 weeks post-surgery (P < 0.05).
Limitations: No signaling inhibitor or genetic manipulation was administered to further confirm
upstream factors of the CREB/BDNF pathway in cognitive deficits caused by chronic trigeminal
neuralgia.
Conclusions: The findings suggest that cognitive impairment caused by cobra venom-induced
trigeminal neuralgia is associated with downregulation of the CREB/BDNF pathway in the
hippocampus and PFC.
Key words: Cognitive impairment, the CREB/BDNF pathway, cobra venom, trigeminal neuralgia,
hippocampus, prefrontal cortex, free behavior, Morris water maze