Rosa × damascena Herrm. and Commiphora wightii (Arn.) Bhandari. combination therapy ameliorates cognitive, neurobehavioral and metabolic impairments in a rat model of Alzheimer's disease through restoration of mitochondrial functions, regulation of neurotransmitter balance and attenuation of pro-inflammatory cytokine levels.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Rosa × damascena Herrm. has been widely employed in Iranian traditional medicine as a nerve tonic to treat anxiety, depression, headache, and other neurological disorders. Additionally, Commiphora wightii (Arn.) Bhandari. (Guggul) is also well recognized in both Ayurvedic and Unani systems, used to treat lipid disorders, obesity, facial paralysis, tremors, and memory loss. AIM OF THE STUDY: Although traditionally used individually, the combination represents a rational multi-target strategy to simultaneously address metabolic and neurodegenerative components associated with Alzheimer's disease (AD). Thus, the present study explored the neuroprotective, metabolic, and behavioral effects of R. damascena and C. wightii combination therapy in a streptozotocin (STZ)-induced rat model of AD. MATERIAL AND METHODS: Adult Wistar rats were administered intracerebroventricular STZ to induce AD-like pathology. A dose-response and combination screening study was initially performed to identify an optimal R. damascena - C. wightii dose pair using normalized escape latency and interaction analysis. The best identified combination and its associated per se doses were then subsequently subjected to detailed behavioral and biochemical evaluations. RESULTS: The interaction-guided analysis identified R. damascena 600 mg/kg + C. wightii 400 mg/kg as the most effective combination and utilized further. While both extracts alone exerted significant protective effects, their combined intervention was more effective in restoring metabolic homeostasis, enhancing motor coordination and exploratory activity, reducing anxiety-like behavior, and improving spatial learning and memory compared to monotherapy, primarily through attenuation of oxidative stress, inhibition of TNF-α-associated neuroinflammatory cascades, restoration of mitochondrial function, and normalization of glutamatergic and cholinergic neurotransmission. CONCLUSION: The findings support this combination as a promising herbal strategy for further investigation in the management of metabolic and cognitive disturbances associated with AD.