Dietary phytochemicals targeting neuroinflammation: mechanisms, bioavailability and translational challenges

Neuroinflammation and oxidative stress are among the most common and fundamental biochemical mechanisms underlying many neurological disorders, and both are promising therapeutic targets. Neuroinflammation and oxidative stress are bidirectional, and each could trigger and amplify the other. Since activated immune cells during neuroinflammation produce high levels of ROS, creating a vicious biochemical cycle, targeting neuroinflammation is an ideal opportunity to curtail both neuroinflammation and oxidative stress. The initiation and progression of neuroinflammation cause structural and functional damage to both neurons and glial cells in the central nervous system. Early intervention to inhibit neuroinflammation could prevent irreversible damage to the nervous tissue. The current application of glucocorticosteroids and nonsteroidal anti-inflammatory drugs in neurological disorders poses a risk of injury to the cardiovascular, gastrointestinal, respiratory, hepatic, and renal systems. Bioactive phytochemicals derived from dietary herbal medicines with demonstrated anti-inflammatory activity could serve as effective substitutes. Although very few of these phytochemicals have undergone clinical trials demonstrating efficacy and safety, several limitations, including lower bioavailability, solubility, and stability, hinder their clinical use. The purpose of this review is to identify preclinical data on multiple dietary bioactive phytochemicals with robust anti-neuroinflammatory effects that could be considered for clinical trials. Based on sufficient, efficacious, predominantly preclinical data, this review highlights the need for future modifications to enhance bioavailability while maintaining or improving therapeutic efficacy, with reduced systemic side effects, for these phytochemicals, rather than evaluating their potency in newer disease models or exploring new mechanisms. Further, prioritizing the identification of top-tier phytochemicals or their combinations that exhibit high bioavailability, optimal dosing, and proven long-term safety, while minimizing drug interactions and systemic toxicity through a standardized set of preclinical studies, is essential to manage chronic neuroinflammation with phytochemicals.