Post-status epilepticus treatment with the Fyn inhibitor, saracatinib, improves cognitive function in mice

Abstract

Background: Status epilepticus (SE) is a life-threatening neurological disorder. The hippocampus, as an important area of the brain that regulates cognitive function, is usually damaged after SE, and cognitive deficits often result from hippocampal neurons lost after SE. Fyn, a non-receptor Src family of tyrosine kinases, is potentially associated with the onset of seizure. Saracatinib, a Fyn inhibitor, suppresses epileptogenesis and reduces epileptiform spikes. However, whether saracatinib inhibits cognitive deficits after SE is still unknown.

Methods: In the present study, a pilocarpine-induced SE mouse model was used to answer this question by using the Morris water maze and normal object recognition behavioral tests.

Results: We found that saracatinib inhibited the loss in cognitive function following SE. Furthermore, we found that the number of hippocampal neurons in the saracatinib treatment group was increased, when compared to the SE group.

Conclusions: These results showed that saracatinib can improve cognitive functions by reducing the loss of hippocampal neurons after SE, suggesting that Fyn dysfunction is involved in cognitive deficits after SE, and that the inhibition of Fyn is a possible treatment to improve cognitive function in SE patients.

Keywords: Cognitive function; Fyn inhibitor; Hippocampal neurons; Saracatinib; Status epilepticus.

Fig. 1

Time depiction of the experimental scheme

Fig. 2

Saracatinib treatment reduces the frequency of epileptic spikes after status epilepticus (SE). a Representative electroencephalogram traces from the hippocampus 14 days after SE. b Quantitative analysis of interictal spikes. c Quantitative analysis of duration of spontaneous seizure. d Quantitative analysis of frequency of spontaneous seizure. Data are expressed as the mean ± SEM (n = 5/group). **p < 0.01

Fig. 3

Saracatinib improves the cognitive function after status epilepticus. Cognitive function was analyzed using the Morris water maze. a Latency to the target platform during a five-day training period. b Distance swum to the target platform during a five-day training period. c Swimming velocity on days 3–5 during the training period. d The number of crossings of the platform site during the probe test. e Time spent in the quadrant of the platform placed in previous locations during the probe test. f, g The cognitive functions were analyzed using the normal object recognition test. f Preference index. (G) Recognition index. Data are expressed as the mean ± SEM (n = 8 or 9/group). *p < 0.05, **p < 0.01. * CON vs SE; # SE vs Sar + SE

Fig. 4

Saracatinib rescues the loss of hippocampal neurons after status epilepticus. a Immunohistochemical detection of NeuN⁺ neurons in the dental gyrus of the hippocampus. b Quantification of NeuN⁺ neurons in each group. Scale bar = 100 µm in lower magnification; = 25 µm in higher magnification insert. Data are expressed as the mean ± SEM (n = 5/group). *p < 0.05, **p < 0.01