Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting nearly 1–2% of the population over 65 years (Dehay et al., 2015). However, about 5–10% experience early-onset forms of PD before 50 years. It is primarily caused by the progressive deterioration of dopaminergic (DAergic) neurons, specifically in the brain's substantia nigra pars compacta region (Dauer and Przedborski, 2003), due to Lewy bodies' formation and unusual aggregation of the alpha-synuclein protein (Cannon et al., 2009). Losing these DAergic neurons leads to dopamine depletion, impairing dopamine signaling. Another important risk factor for the degeneration of DAergic neurons in PD is cellular oxidative stress, an imbalanced state due to impaired mitochondrial function and elevated reactive oxygen species (ROS) inside the cell (Bandopadhyay and de Belleroche, 2010). Neuronal cellular models are frequently used to investigate PD and its therapeutic neuroprotective agents. The most commonly used cellular model for PD research is the human SH-SY5Y neuroblastoma cells with several characteristics similar to DAergic neurons, such as the expression of the dopamine transporter, dopamine-beta-hydroxylase, tyrosine hydroxylase, and various other growth factor receptors (Xie et al., 2010). Many studies suggest that exposure to pesticides such as rotenone (ROT) may increase the risk of PD due to mitochondrial dysfunction (Gorell et al., 1998). ROT, a naturally occurring isoflavonoid derived from plants and a commonly used pesticide, is a potent inhibitor of the enzyme NADH ubiquinone reductase of the mitochondrial complex I electron transport chain (ETC). It has been used as a neurotoxin that induces cell death in DAergic neurons specifically by limiting ATP production and its supply, thereby mimicking the symptoms of PD (Sherer et al., 2007; Greenamyre et al., 2003; Alam and Schmidt, 2002; Betarbet et al., 2000).

Currently, there is no complete treatment for PD, and the available treatment strategies are symptomatic. However, some therapies, like dopamine-replacement therapies, increase dopamine in the nervous system, enhance dopaminergic cell survival, and reduce PD symptoms to sustain the quality of patients’ lives. Unfortunately, the long-term use of these existing therapies has adverse effects. Besides, these treatments cannot halt or even delay neurodegenerative processes (Zahoor et al., 2018). Therefore, it is crucial to discover novel drugs that slow the progression of PD. Scientists are now attracted by plants with high antioxidant value as a primary target for exploring such medications because of their phytochemical constituents, which have immense therapeutic potential against several disease conditions.

Three medicinal plants - Alternanthera sessilis (L.) R. Br. ex DC. (Amaranthaceae), Eryngium foetidum (Apiaceae) L., and Stephania japonica (Thunb.) Miers (Menispermaceae), traditionally used in treating nervous system-related disorders or implicated in other ailments, were selected for the study. Alternanthera sessilis, locally known as Phakchet in Manipuri, is consumed as a vegetable weed in many Asian countries, particularly in South India. A. sessilis is a folkloric medicinal plant of Manipur, used in dealing with different disease conditions. The whole plant decoction of A. sessilis is used for treating paralysis, root decoction for dysentery, and whole plant paste for boils (Devi et al., 2023). The decoction of the whole plant is also used to promote memory (Shiddamallayya et al., 2010) and intelligence (Anupam et al., 2016) and as an energizer to eliminate fatigue, laziness, and sleep (Mondal et al., 2014). The whole plant of A. sessilis is also used to alleviate pain (Tan and Kim, 2013), headaches, dizziness (Arshad et al., 2011), neuralgia (Saqib and Janbaz, 2016), and burning sensation (Sharma and Joshi, 2018). Furthermore, a thick paste from crushing fresh plants is used for sprains and skin inflammation (Sahithi et al., 2011). In China, a decoction of the herb with wine is used for internal injuries, and soup made from the plant with meat is taken to treat tuberculosis (DeFilipps and Krupnick, 2018). Phytochemical examination of the plant A. sessilis revealed the presence of ionone derivatives (Ragasa et al., 2002), vanillic acid, ferulic acid, apigenin, chlorogenic acid, 4-hydroxybenzoic, ethyl gallate, daidzein, epigallocatechin (Othman et al., 2016), beta-sitosterol (Gupta and Singh, 2012). It is further reported to contain gallic acid (Gupta and Singh, 2016), ellagic acid, quercetin, catechin, rutin (Mondal et al., 2014), phytosterols (Kota et al., 2017), flavonoids like 3′, 3, 6, 7-tetramethoxy - 4′, 5, 8-trihydroxy flavones (Das et al., 2017), oleic acid, lup-20 (29)-en-3-one, propylene glycol monooleate, phytol, esters (Suganya et al., 2019) and saponins (Lalitha and Vijayalakshmi, 2018). A. sessilis is also a rich source of beta-carotene, vitamins (A, B, C, and E) (Lalitha and Vijayalakshmi, 2018). A. sessilis is also reported to have high protein, calcium, potassium, magnesium, iron, and other macro and micro elements (Umate and Marathe, 2018; Othman et al., 2016).

E. foetidum (local name Awa phadigom), commonly known as spiny coriander, is a small aromatic flavoring plant native to Mexico and South America and is widely cultivated in Manipur. Traditionally, the decoction or paste made from fresh leaves of the plant is used to cure paralysis and epilepsy by the Meitei ethnic community of Manipur, India (Devi et al., 2017, 2021; Das and Tongbram, 2014). The paste of E. foetidum whole plant is used in muscular sprain, vertigo, hypertension, fever, cough, ulcer, cuts and injuries, dyspepsia, diarrhea, dysentery, arthritis, body ache, skin diseases, bone fracture, and vomiting (Devi et al., 2021). The leaves of E. foetidum are eaten to relax convulsions due to high fever (Nath et al., 2021), and the whole plant is used to treat seizures and anxiety (Rodrigues et al., 2022). The crushed leaf is also used for body pain (Seraj et al., 2013). The medicinal value of E. foetidum is supported by the presence of varied phytochemicals in the plant. E. foetidum contains Eryngial (trans-2-dodecenal) as a major constituent in leaves and 2,3,4-trimethylbenzaldehyde in roots (Rodrigues et al., 2022). The essential oil of E. foetidum contains volatile aromatic aldehydes, fatty acids, aliphatic aldehydes, and terpenoids (Rodrigues et al., 2021; Thomas et al., 2017; Chandrika et al., 2015; Jaramillo et al., 2011; Rana, 2008; Chowdhury et al., 2007; Cardozo et al., 2004). Phytosterols such as stigmasterol, delta (5)24-stigmastadienol, β-sitosterol, alpha-cholesterol, clerosterol, brassicasterol, campesterol, delta 5-avenasterol, delta 7-avenasterol, were also present in the leaves of E. foetidum (García et al., 1999). A daucane sesquiterpene - lasidiol p-methoxybenzoate and a terpene aldehyde ester derivative: 4-hydroxy-1,1,5-trimethyl-2-formyl-cyclohexadien-(2,5)-[α-acetoxymethyl-cis-crotonate], were isolated from the seed of the plant (Rojas-Silva et al., 2014). The plant has lutein, β-carotene, chlorogenic acid, kaempferol and caffeic acid (Mekhora et al., 2012), feruloylquinic acid, ferulic acid derivative, quercetin glucuronide, luteolin hexoside, luteolin glucuronide (Leitão et al., 2023), coumarins and sesquiterpene lactones (Saravia-Otten et al., 2022), carotenoids (Suttisansanee et al., 2023), tannin (Bhavana et al., 2013), saponins, alkaloids, anthraquinones, and cardiac glycosides (Okon et al., 2013).

The third plant, S. japonica (locally known as Thangga-uri angouba), commonly called snake vine, is a widely grown climber plant in Manipur, India. The leaf paste of the plant has been used traditionally to treat facial paralysis (Yusuf et al., 2007) and is applied externally to have mental peace (Hossain and Rahman, 2018). Leaf extract of S. japonica is used to cure skin inflammation (Devi and Das, 2015). The crushed leaf or whole plant is used for severe body pain (Seraj et al., 2013) and sprain (Jahan et al., 2010). The leaf and root of S. japonica are also used in asthma, chest pain, gastritis, diarrhea, dysentery, fever, itches, tropical ulcers, stomachaches, and urinary diseases (Rudra et al., 2021). The leaf decoction treats vertigo, paralysis, and other mental disorders (Uddin and Zidorn, 2020). The plant's root treats stroke and fever (Xiao et al., 2019). The sticky mass prepared from its leaves is applied to breast infections, leaf paste to septic inflammation and boils, and the decoction is drunk as rejuvenating drinks (Handique and Sharma, 2010). The plant contains bisbenzylisoquinoline alkaloids - isotrilobine, trilobine (Hall and Chang, 1997), cepharanthine (Lin et al., 2019), proaporphine alkaloid - stepharine (Xiao et al., 2019), hasubanan alkaloids - stephalonine E, N-methylstephisoferulin, 6-cinnamoylhernandine, aknadinine, longanine, aknadilactam, N-methylstephuline, prostephabyssine (Carroll et al., 2010), stephalonine L, stephalonine M, stephalonine N, stephalonine O, epistephamiersine (Xiao et al., 2019), morphinane alkaloid (sinococuline) (Carroll et al., 2010), undescribed alkaloids - stephalonine P, 6,7-didehydro-3,4,7-trimethoxy-17-methyl-8-oxohasubanan, stephamiersine, delavayine, stephavanine, dihydroepistephamiersine, prometaphanine, prostephabyssine, epistephanine (Xiao et al., 2019). Polyphenolic compounds such as epicatechin, p-coumaric acid, rutin hydrate, caffeic acid, and quercetin are present in S. japonica. Phytochemicals like tannin, proanthocyanidins, lycopene, chlorophylls a and b, flavonoids, carotenoids (Uddin et al., 2016), steroids, glycoside (Rahman et al., 2011), saponins, and triterpenes (Sultana et al., 2012) are also present in the plant.

Some studies have reported the antidepressant, CNS stimulant, and nootropic activity of A. sessils, anti-neuroinflammatory in the middle cerebral artery occlusion (MCAO) rat model of ischemic stroke, anticholinesterase, and memory-enhancing potentials of S. japonica. However, numerous studies have reported the antioxidant, anti-inflammatory, anticancer, antidiabetic, antidiarrheal, analgesic, antibacterial, and many other pharmacological activities of these plants. Although these plants have been used traditionally in many neurological-related ailments as drugs (seizures, convulsions, paralysis, epilepsy) or as a tonic (eliminate laziness, fatigue, vertigo, and tiredness), there is no scientific report on their neuroprotective activities. Therefore, the present study aimed to explore the neuroprotective potential of these three medicinal plants against rotenone-induced neurotoxicity in SH-SY5Y cells as a PD model.