## 1 Introduction  
Neurodegenerative diseases (NDDs) and multifactorial deliberation diseases caused by structural and functional neuronal anomalies in the central nervous system (CNS). NDDs are typified by persistent degeneration of neurons in the CNS, which may lead to physical disabilities and psychobehavioral manifestations including ataxia and dementia [1]. Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and Huntington's disease (HD) are examples of classic NDDs. Although partially attributable to the expansion of life, a discernible increase in the prevalence of NDDs has been noticed during the past ten years [2; 3]. Importantly, many of the presently approved drug regimens alleviate symptoms but neither cure nor prevent the propagation of neurodegenerative diseases [4]. Additionally, the prognosis is poor for most NDDs due to the lack of effective therapies. Moreover, the complications of current therapies and the deterioration of the therapeutic efficacy over time have further increased the demand for discovering safe and efficacious treatment modalities for NDDs. Although there are key pathophysiological differences, microglial activation and chronic neuroinflammation are pathological hallmarks in most NDDs [5; 6]. Pathogenesis of AD is not restricted to the neuronal compartment and is strongly related to the innate immune response triggered by microglia. The identification of amyloid-\(\beta\) (A\(\beta\)) species by pattern recognition receptors (PRRs) on microglia enhances the expression of cytokines and mediators that are responsible for neuroinflammation, including nitric oxide (NO), tumor necrosis factor-alpha (TNF-\(\alpha\)), and interleukin-6 (IL-6), through activation of nuclear factor-\(\kappa\)B (NF-\(\kappa\)B) via toll-like receptor (TLR) signaling pathways. The chronic overabundant production of pro-inflammatory cytokines further enhances neuronal damage and induces the upregulation of \(\beta\)-secretase, which is responsible for the production of pathogenic A\(\beta\) species [7]. In Parkinsonism, chronic release of proinflammatory cytokines from activated microglia is considered a key contributor to the deterioration of dopaminergic neurons in the substantia nigra pars compacta [8]. Therefore, proinflammatory cytokines released from activated microglia have a crucial involvement in the initiation and perpetuation of neurodegeneration and attenuation of chronic neuroinflammation, and proinflammatory cytokine expression is considered to produce a therapeutic benefit in NDDs [9; 10]. Pytochemicals have captured significant interest as neuroprotective agents. The therapeutic efficacy of phytochemicals is mainly attributed to their antioxidant, anti-inflammatory, and antichoinesterase activities [2]. _Acmella paniculata_ (Wall ex DC.) [PERSON], from the plant family Asteraceae, is a versatile medicinal plant with a plethora of nephopharmaceutical applications. _A. paniculata_ is known to possess a variety of bioactivities including local anesthetic, antimicrobial, anti-unjuretic, antioxidant, anti-inflammatory, insecticidal, anticancer, and larvicidal activity [11; 12; 13]. Floral inflorescence of _A. paniculata_ is a rich source of N-alkylamides, and the fresh floral inflorescence has been widely used in many traditional medical systems to alleviate pain and inflammation and to induce local anesthesia. Spilanthol [(2E,6Z,8E)-N-Isobutyldeca-2,6,8-trienamide] is one of the most prominent biologically active N-alkylamides in the infloresence of _A. paniculate_[14]. Spilanthol is renowned for its bioactivities, including anti-fungal, anti-inflammatory, anti-noociceptive, local anesthetic, and aphrodisiac activity [15]. Although a few studies have been conducted to evaluate the anti-neuroinflammatory effectiveness of spillanthol, the specific mechanism through which it confers neuroprotection remains unclear.