Contents lists available at ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr Research paper Transcranial direct current stimulation alleviates seizure severity in kainic acid-induced status epilepticus rats Yi-Jen Wu a,b, ⁎ , Miao-Er Chien a , Chih-Hsu Huang b , Chia-Chu Chiang c , Chou-Ching Lin b , Chin-Wei Huang b , Dominique M. Durand c , Kuei-Sen Hsu d,e, ⁎⁎ a Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70457, Taiwan b Department of Neurology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan c Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA d Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan e Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan ARTICLE INFO Keywords: Status epilepticus Seizure Electroencephalography Mossy fiber sprouting Brain-derived neurotrophic factor Transcranial direct current stimulation ABSTRACT Status epilepticus (SE) is a state of prolonged and repeated seizures that can lead to permanent brain damage or life-threatening conditions. Transcranial direct current stimulation (tDCS) non-invasively provides a polarity- specific electric current to modulate brain excitability. Little is known about the therapeutic potential of tDCS in SE. Here, we aim to determine the tDCS effects on seizure severity, EEG and post-SE consequences in rats with kainic acid (KA)-induced SE. Rats were subjected to cathodal tDCS or sham stimulation over the dorsal hip- pocampus for 5 days. KA was intraperitoneally injected to induce SE. We used continuous video-EEG recording to monitor seizure activity, immunostaining and Timm staining to evaluate neuron counts and mossy fiber sprouting, and ELISA for Brain-derived neurotrophic factor (BDNF) protein measurement. Two featured EEG patterns, gamma ranged high-frequency polyspikes and low-frequency spike-and-wave complexes, were iden- tified in the hippocampal CA1 of KA-induced SE rats. tDCS elicited a significant decrease in severe seizures of Racine stages 4–5 in KA-induced SE rats. tDCS-treated rats manifested diminished high-frequency oscillation during SE, decreased chronic spontaneous spike activities and mossy fiber sproutings compared to sham. tDCS- treated rats also exhibited significantly lower hippocampal BDNF protein levels than sham immediately and 4 weeks after SE. A positive correlation between the hippocampal BDNF level and the seizure severity of SE was found. Altogether, our results show that repeated cathodal tDCS can mitigate seizure severity, alter ictal EEG pattern and reduce the chronic adverse consequences in KA-induced SE rats, supporting the therapeutic potential of tDCS in severe prolonged epileptic seizures. 1. Introduction Status epilepticus (SE) is a relatively common and potentially life- threatening neurological emergency characterized by prolonged or re- current seizures. The annual incidence of SE is estimated to be 10–41 per 100,000 persons and the mortality of SE is 20% (Coeytaux et al., 2000; DeLorenzo et al., 1995; Knake et al., 2001). Patients with SE may have high complication (Kamppi et al., 2018) and demand complicated medical care and cost (Penberthy et al., 2005). Although the exact cellular mechanisms responsible for the development of SE remain unclear, it appears to be associated with the excessive abnormal excitation during a seizure or the loss of endogenous inhibitory me- chanisms (Betjemann and Lowenstein, 2015). Current available treat- ments for SE such as benzodiazepines, anti-epileptic drugs and general anesthetics are not universally effective. In 23–43% of the patients with SE, seizures persisted despite administration of benzodiazepines and anti-epileptic drugs (Mayer et al., 2002; Pugin et al., 2014). Given the relatively common incidence, high complication and mortality, as well as the unsatisfactory treatment options for SE, there is an urgent need to identify additional effective treatments and neuromodulation is con- sidered to be a potential therapeutic method (San-Juan et al., 2015). Transcranial direct current stimulation (tDCS), a non-invasive https://doi.org/10.1016/j.expneurol.2020.113264 Received 17 February 2020; Accepted 28 February 2020 ⁎ Correspondence to: Y. J. Wu, Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 35, Xiaodong Rd., Tainan City 70457, Taiwan. ⁎⁎ Correspondence to: K. S. Hsu, Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Rd., Tainan City 70101, Taiwan. E-mail addresses: wuyj@mail.ncku.edu.tw (Y.-J. Wu), richard@mail.ncku.edu.tw (K.-S. Hsu). Experimental Neurology 328 (2020) 113264 Available online 29 February 2020 0014-4886/ © 2020 Elsevier Inc. All rights reserved. T