Ferrostatin-1 mitigates cognitive impairment of epileptic rats by inhibiting P38 MAPK activation

https://doi.org/10.1016/j.yebeh.2019.106670Get rights and content

Highlights

  • Ferrostatin-1 represses P38 MAPK activation and mitigate synaptic proteins deficits and cognitive deficits in rats with KA induced TLE.

  • SB203580 improve cognitive function in rats with KA induced TLE.

  • P38 MAPK activation mediates synaptic proteins deficits in rats with KA induced TLE.

Abstract

Evidence indicates that ferrostain-1 (Fer-1), a specific inhibitor of ferroptosis, could ameliorate cognitive dysfunction of rats with kainic acid (KA)-induced temporal lobe epilepsy (TLE) by suppressing ferroptosis processes. Recent studies suggest that P38 mitogen-activated protein kinase (MAPK) pathway could be mediated by ferroptosis processes. The activation of P38 MAPK results in cognitive impairment by suppressing the expression of synaptic plasticity-related proteins. However, it is unclear whether Fer-1 can mitigate cognitive impairment of rats with KA-induced TLE by inhibiting P38 MAPK activation. In the present study, treatment with Fer-1 blocked the activation of P38 MAPK, which resulted in an increased expression of synaptophysin (SYP) and postsynaptic density protein 95 (PSD-95) in the hippocampus of rats with KA-induced TLE, hence, ameliorating their cognitive impairment. Also, P38 MAPK activation in the hippocampus of the rats reduced the expression of both PSD-95 and SYP proteins. Treatment of the rats with SB203580, a P38 MAPK-specific inhibitor, prevented the activation of P38 MAPK, which resulted in an increase in SYP and PSD95 protein levels in the hippocampus. These results suggest that Fer-1 could mitigate the cognitive impairment by suppressing P38 MAPK activation thus restoring the expression of synaptic proteins. Ferroptosis processes might be involved in suppressing synaptic protein expression.

Introduction

Cognitive dysfunction is one of the most common comorbidities of temporal lobe epilepsy (TLE). About 50% of patients with epilepsy are deficient in one or more cognitive abilities, and this affects their quality of life [1]. Synaptic plasticity is the molecular mechanism of learning and memory. Several lines of evidence confirm that synaptic plasticity impairment plays a crucial role in cognitive comorbidities of TLE [2,3]. Studies have indicated that synaptic proteins, such as, synaptophysin (SYP) and postsynaptic density protein 95 (PSD-95), can act as markers of synaptic plasticity [4,5]. The reduction of hippocampal SYP and PSD-95 levels results in cognitive impairment of rats with kainic acid (KA)-induced epilepsy [[6], [7], [8]].

The P38 mitogen-activated protein kinase (MAPK) pathway activation results in synaptic plasticity impairment and mediates cognitive dysfunction in Alzheimer's disease. The activation of P38 MAPK leads to a decrease in the expression of SYP and PSD-95, and this could cause cognitive dysfunction [9,10]. Emerging evidence suggests that P38 MAPK activation can be mediated by ferroptosis processes [11]. Our previous study demonstrated that ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, can improve cognitive function of rats with KA-induced TLE by inhibiting hippocampal neuronal ferroptosis [12]. In the current study, it was speculated that Fer-1 could mitigate cognitive comorbidities of TLE by suppressing P38 MAPK activation hence restoring the expression of hippocampal synaptic plasticity-related proteins.

This study aimed to confirm whether Fer-1 could upregulate the expression of hippocampal SYP and PSD-95 by inhibiting the activation of P38 MAPK, thus, contributing to the improvement of the cognitive function of rats with KA-induced TLE. Also, the study was to determine whether P38 MAPK activation can reduce the expression of hippocampal SYP and PSD-95 of rats with KA-induced TLE, and result in cognitive dysfunction.

Section snippets

Animal treatments

All experiments were conducted on adult male Sprague–Dawley rats (200 g–220 g, n = 80), obtained from Hunan Slake Jingda Laboratory Animal Co., Ltd. (Changsha, China). Each rat was kept in a separate cage in a temperature-controlled room under a 12-hour light/dark cycle (lights on at 07:00 a.m.) and with free access to food and water. All animal experiments were performed according to the National Institutes of Health's “Guide for the Care and Use of Laboratory Animals.” This work was approved

Fer-1 attenuates cognitive impairment of rats with KA-induced TLE

To assess cognitive function, rats were subjected to the MWM tests. The results of spatial navigation tests showed that the escape latency and the swimming distance decreased progressively in experimental rats of all groups during the five training days. From the second day onwards, the escape latency and the swimming distance of the KA + vehicle group were higher than that of the sham + vehicle group (P < .05) (Fig. 2A, Fig. 2B). From the third day onward, the escape latency and the swimming

Discussion

Synaptic plasticity is one of the critical processes in learning and memory regulation [21]. Strengthening and weakening of synaptic connections are regulated by a series of neurochemical alterations that are critical in the process of synaptic plasticity [22]. These neurochemical alterations include the following: synaptic insertion and removal of glutamate receptors, changes in neurotransmitters release, and structural changes in dendritic spines. These alterations are regulated by synaptic

Conclusions

Ferrostatin-1 mitigates cognitive impairment of rats with KA-induced TLE by inactivating P38 MAPK, thus, restoring the expression of hippocampal SYP and PSD95, and ferroptosis processes might be involved in synaptic protein suppression.

Declaration of competing interest

The authors declare that they have no conflicts of interest regarding this article.

Acknowledgment

This work was supported by grants from National Natural Science Foundation of China (grant Nos: 81760242).

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