Geraniol and Z-guggulsterone co-treatment attenuates Alzheimer's disease in adult zebrafish by targeting oxidative damage, neuroinflammation, mitochondrial stress, and synaptic dysfunction.

Given the multifactorial pathogenesis of Alzheimer's disease (AD) and the limited efficacy of single-target drug therapy, there is a growing scientific need for combination regimens to concurrently target various AD-associated cascades. Currently, plant-derived phytoconstituents, with their intrinsic multi-target properties, represent a promising component for combination therapy, offering translational potential with enhanced neuroprotection. In this avenue, the current study aimed to explore the combined neuroprotective effects of geraniol (a monoterpenoid alcohol) and Z-guggulsterone (a phytosterol) in streptozotocin (STZ)-induced AD model of adult zebrafish (4-6 months old). Following intracerebroventricular STZ injection, zebrafish were treated with geraniol and Z-guggulsterone per se and in combination for 28 consecutive days. On day 27, a novel tank diving test and a light/dark preference test were performed to evaluate locomotive and cognitive impairments. Afterwards, the fish were evaluated for numerous blood parameters, including blood glucose and serum cholesterol levels, followed by biochemical assessment of oxidative stress markers, mitochondrial complexes, neuroinflammatory cytokines, and neurotransmitter levels. Results demonstrated that co-therapy of geraniol and Z-guggulsterone significantly ameliorated cognitive deficits, reduced anxiety-like behaviours, impeded acetylcholinesterase activity, regulated neurotransmitter levels (glutamate and acetylcholine), mitigated oxidative stress markers, and prevented mitochondrial dysfunction, compared to monotherapies. Additionally, downregulation of TNF-α was also observed, affirming suppression of detrimental neuroinflammatory processes. Collectively, these findings support the neuroprotective potential of geraniol and Z-guggulsterone co-therapy in the zebrafish model of AD; however, future research is warranted to explore the potential clinical application of this combination therapy in AD.