Investigating the neuroprotective effects of Dracocephalum moldavica extract and its effect on metabolomic profile of rat model of sporadic Alzheimer's disease

Alzheimer's disease (AD) is a progressive condition marked by multiple underlying mechanisms. Therefore, the investigation of natural products that can target multiple pathways presents a potential gate for the understanding and management of AD. This study aimed to assess the neuroprotective effects of the hydroalcoholic extract of <i>Dracocephalum moldavica</i> (DM) on cognitive impairment, biomarker changes, and putative metabolic pathways in a rat model of AD induced by intracerebroventricular streptozotocin (ICV-STZ). The DM extract was standardized and quantified based on examining total phenolic, total flavonoid, rosmarinic acid, and quercetin contents using colorimetry and high-performance liquid chromatography (HPLC) methods. The antioxidant potential of the extract was evaluated by 2,2-Diphenyl-1-picrylhydrazyl and nitric oxide radical scavenging assays. Male Wistar rats were injected with STZ (3 mg/kg, single dose, bilateral ICV) to induce a sporadic AD (sAD) model. Following model induction, rats were orally administered with DM extract (100, 200, and 400 mg/kg/day) or donepezil (5 mg/kg/day) for 21 days. Cognitive function was assessed using the radial arm water maze behavioral test. The histopathological evaluations were conducted in the cortex and hippocampus regions. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) was used to assess metabolite changes in various brain regions. DM extract significantly attenuated cognitive dysfunction induced by ICV-STZ according to behavioral and histopathological investigations. Thirty-two discriminating metabolites related to the amino acid metabolism; the glutamate/gamma-aminobutyric acid/glutamine cycle; nucleotide metabolism; lipid metabolism (glycerophospholipids, sphingomyelins, ceramides, phosphatidylserines, and prostaglandins), and glucose metabolic pathways were identified in the brains of rats with sAD simultaneously for the first time in this model. Polyphenols in DM extract may contribute to the regulation of these pathways. After treatment with DM extract, 10 metabolites from the 32 identified ones were altered in the brain tissue of a rat model of sAD, most commonly at doses of 200 and 400 mg/kg. In conclusion, this study demonstrates the neuroprotective potential of DM by upregulation/downregulation of various pathophysiological biomarkers such as adenine, glycerophosphoglycerol, inosine, prostaglandins, and sphingomyelin induced by ICV-STZ in sAD. These findings are consistent with cognitive behavioral results and histopathological outcomes.