Epilepsy is a chronic neurological condition presented by seizures due to abnormal neuronal firing. It dramatically affects the quality of life of epileptic patients due to additional adverse effects of recurrent seizures on other body systems (Beghi, 2020). The seizures also disrupt the autonomic functions that affect the respiratory and cardiovascular systems (Manolis et al., 2019). Cardiac arrhythmias are the most prominent heart abnormality observed in epilepsy patients (Asatryan, 2021). There is an aberration in proxy stimulation of the autonomic afferents due to chronic seizures that result in heart rate variability, especially in juvenile myoclonic and temporal lobe epilepsy patients (Tomson et al. 1998; van der Lende et al., 2016). Epilepsy-associated cardiac arrhythmias are also related to prolonged QT interval, which is linked with an increased expression of neuronal sodium channels in the heart (Biet et al., 2015). Seizure-linked cardio-respiratory function variations have been associated with sudden unexpected death in epilepsy (SUDEP) (Stöllberger and Finsterer, 2004; Aiba and Noebels, 2015; Katayama, 2020). Despite underestimating epilepsy-related mortality in older adults, the available literature shows a high incidence of SUDEP, accounting for around 8 to 17 percent of the total cases (Manolis et al., 2019). The impact of conventional antiepileptic drugs on SUDEP is not fully understood. Moreover, a few of these agents have been suggested to increase the risk of SUDEP due to their direct effect on cardiac rhythm and other autonomic functions (Aurlien et al., 2016). There is a need for some potential agents that can inhibit epileptic seizures and prevent associated cardiac irregularities (O'Neal et al., 2022). However, the lack of information regarding the exact pathogenesis of SUDEP has primarily affected the development of therapeutic interventions for its management (Maguire et al., 2016).

Recent studies have identified some potential molecular pathways that can be targeted to reduce the risk of SUDEP. A preclinical study involving transcriptomic and proteomic analysis found 1264 differentially expressed proteins and 1157 differentially expressed genes, respectively, in the cardiac tissue of epileptic rats (Sharma et al., 2021a). The study showed an upregulation of the mammalian target of rapamycin (mTOR) as a crucial pathogenic event related to recurrent seizures-mediated cardiac irregularities. The mTOR is a serine/threonine kinase involved in cellular homeostasis, energy regulation and plays a crucial role during stress (Haissaguerre et al., 2014). It is mainly involved in protein synthesis, transcription, cell proliferation, survival, growth, motility, and autophagy (Saxton and Sabatini, 2017). The physiological functions of mTOR are mediated via its interaction with mTORC1 and mTORC2 multiprotein complexes. Its role has been well studied in different diseased conditions like obesity, cardiovascular diseases, metabolic diseases, genetic abnormalities, and neurological disorders (Laplante and Sabatini, 2012). The role of mTOR pathway hyperactivation has also been well explored in the pathogenies of epilepsy (Mazumder et al., 2016). Hence, all these literature findings suggested that mTOR inhibition is a potential target for suppressing epileptic seizures and linked cardiac irregularities leading to SUDEP.

Nardostachys jatamansi (D.Don) DC. (N. jatamansi) is a perennial herbaceous medicinal plant commonly known as “Jatamansi” or “Balchar” (Purnima et al., 2015). It belongs to the family Caprifoliaceae and is enlisted as critically endangered in International Union for Conservation of Nature List of Threatened Species. It commonly grows in moist and sloppy areas and is native to India, Nepal, China, Bhutan, and Tibet (Dhiman and Bhattacharya, 2020). Its roots and rhizomes are widely used for a various neurological, cardiovascular, gastrointestinal, and skin conditions in Ayurveda, Sidha, and Unani systems of medicine (Nithya and Muthuraman, 2016). In ancient times N. jatamansi was used to treat epilepsy by Susrata (Father of Indian Surgery) (Dhiman and Bhattacharya, 2020). The rhizomes of N. jatamansi are also used as an antispasmodic, bitter tonic, antihysteric and antiepileptic in the Ayurvedic system of medicine (Bhatt and Kothiyal, 2015). The roots and rhizome of N. jatamansi contains several coumarins and sesquiterpenes. The major compounds identified include valeranone, jatamansin, spirojatamol, calarenol jatamols (A and B), and nardostachysin (Rao et al., 2012). Scientific studies showed antioxidant, hepatoprotective, cardiotonic, antihyperlipidemic, antimicrobial, antihyperglycemic, antiarrhythmic, antidepressant, anticonvulsant and neuroprotective activities of N. jatamansi (Ahmad et al., 2013).

N. jatamansi ethanolic root extract increased the seizure threshold in the maximal electroshock seizure rat model and increased the protective index of simultaneous phenytoin treatment (Rao et al., 2005). Another root extract of N. jatamansi showed seizure protection in maximal electroshock and along pentylenetetrazole convulsion rat models (Purushotham and Basavanna, 2016). Several earlier studies have shown the cardioprotective effects of roots and rhizomes of N. jatamansi and their effectiveness in other cardiovascular abnormalities (Subashini et al., 2006; Bhat and Malik, 2020). Hence, based on the available information, the present study was performed to explore the effectiveness of N. jatamansi in a chronic model of epilepsy and its associated cardiac irregularities.