Epilepsy is a devastating condition affecting around 70 million people worldwide. Moreover, the quality of life of people with epilepsy (PWE) is worsened by a series of comorbidities. The neurobehavioral comorbidities discussed herein share a reciprocal and complex relationship with epilepsy, which ultimately complicates the treatment process in PWE. Understanding the mechanistic pathway by which these comorbidities are associated with epilepsy might be instrumental in developing therapeutic interventions. Inflammatory cytokine signaling in the brain regulates important brain functions including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, dopaminergic transmission, the kynurenine pathway, and affects neurogenesis as well as the neural circuitry of moods. In this review, we hypothesize that the complex relationship between epilepsy and its related comorbidities (cognitive impairment, depression, anxiety, autism, and schizophrenia) can be unraveled through the inflammatory mechanism that plays a prominent role in all these individual conditions. An ample amount of evidence is available reporting the role of inflammation in epilepsy and all individual comorbid condition but their complex relationship with epilepsy has not yet been explored through the prospective of inflammatory pathway. Our review suggests that epilepsy and its neurobehavioral comorbidities are associated with elevated levels of several key inflammatory markers. This review also sheds light on the mechanistic association between epilepsy and its neurobehavioral comorbidities. Moreover, we analyzed several anti-inflammatory therapies available for epilepsy and its neurobehavioral comorbidities. We suggest, these anti-inflammatory therapies might be a possible intervention and could be a promising strategy for preventing epileptogenesis and its related neurobehavioral comorbidities.
1. Andrographis paniculata (Burm. f) Nees, commonly known as 'king of bitters', is a herbaceous plant belonging to the Family Acanthaceae. It has been widely used for centuries in Asian countries like China, India, Thailand and Malaysia for the treatment of sore throat, flu and upper respiratory tract infections. 2. Andrographolide, 14-deoxy-11,12-didehydroandrographolide and neoandrographolide are examples of the major labdane diterpenoids isolated from A. paniculata. These bioactive molecules have exhibited varying degrees of anti-inflammatory and anticancer activities in both in vitro and in vivo experimental models of inflammation and cancer. 3. Extensive libraries of andrographolide analogues have been synthesised mainly by modifying the α,β-unsaturated γ-butyrolactone moiety, the two double bonds Δ(8,(17)) and Δ(12,(13)) and the three hydroxyls at C-3 (secondary), C-14 (allylic) and C-19 (primary). Many of these synthetic analogues exhibit superior anticancer activity over the naturally occurring andrographolides. 4. Andrographolide and its derivatives have been shown to have anti-inflammatory effects in experimental models of asthma, stroke and arthritis, as well as in patients with upper respiratory tract infections. Andrographolide reduces the production of cytokines, chemokines, adhesion molecules, nitric oxide and lipid mediators, probably via inhibition of the nuclear factor (NF)-κB signalling pathway. 5. The anticancer mechanisms for andrographolide include inhibition of Janus tyrosine kinases-signal transducers and activators of transcription, phosphatidylinositol 3-kinase and NF-κB signalling pathways, suppression of heat shock protein 90, cyclins and cyclin-dependent kinases, metalloproteinases and growth factors, and the induction of tumour suppressor proteins p53 and p21, leading to inhibition of cancer cell proliferation, survival, metastasis and angiogenesis. 6. Andrographolide drug discovery is a promising strategy for the development of a novel class of anti-inflammatory and anticancer drugs.