Phytotherapeutic modulation of hypothalamic –pituitary adrenal (HPA) axis in neurological disorders - preclinical evidence and clinical perspectives

Abstract Neurological disorders, including Alzheimer’s disease, Parkinson’s disease, depression, anxiety, and epilepsy, involve complex pathological mechanisms such as oxidative stress, neuroinflammation, mitochondrial dysfunction, neurotransmitter imbalance, and neuronal loss. Increasing evidence indicates that dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis plays a crucial role in their pathogenesis. Chronic stress-induced HPA-axis activation results in excessive glucocorticoid release, promoting cognitive impairment, neuroinflammation, and neurodegeneration. Although conventional therapies provide symptomatic relief, their long-term efficacy is often limited by adverse effects. Consequently, phytotherapeutics have gained attention as promising complementary interventions because of their multitarget neuroprotective properties and favorable safety profiles. This review highlights the role of HPA-axis dysfunction in neurological disorders and explores the therapeutic potential of plant-derived bioactive compounds in restoring neuroendocrine homeostasis. Phytochemicals such as curcumin, resveratrol, quercetin, epigallocatechin gallate, bacosides, withanolides, and ginsenosides exhibit beneficial effects by modulating glucocorticoid signaling, reducing oxidative stress and neuroinflammation, enhancing neurotrophic factors, and regulating neurotransmitter systems. Evidence from preclinical and emerging clinical studies supports their ability to improve neurological function and stress resilience. Furthermore, advances in nano-phytomedicine may improve the bioavailability and brain-targeted delivery of phytotherapeutic agents, enhancing their therapeutic potential. Overall, phytotherapeutics represent promising supportive strategies for managing neurological disorders associated with HPA-axis dysregulation. KeywordsPhytotherapeutics, HPA Axis, Neurological disorders, Neuroprotection