Thymol inTrachyspermum ammiseed extract exhibits neuroprotection, learning, and memory enhancement in scopolamine‐induced Alzheimer's disease mouse model

Abstract

Several reports have stated the neuroprotective and learning/memory effects of Tachyspermum ammi seed extract (TASE) and its principal component thymol; however, little is known about its underlying molecular mechanisms and neurogenesis potential. This study aimed to provide insights into TASE and a thymolmediated multifactorial therapeutic approach in a scopolamine-induced Alzheimer's disease (AD) mouse model. TASE and thymol supplementation significantly reduced oxidative stress markers such as brain glutathione, hydrogen peroxide, and malondialdehyde in mouse whole brain homogenates. Tumor necrosis factor-alpha was significantly downregulated, whereas the elevation of brain-derived neurotrophic factor and phospho-glycogen synthase kinase-3 beta (serine 9) enhanced learning and memory in the TASE-and thymol-treated groups. A significant reduction in the accumulation of Aβ 1-42 peptides was observed in the brains of TASE-and thymol-treated mice. Furthermore, TASE and thymol significantly promoted adult neurogenesis, with increased doublecortin positive neurons in the subgranular and polymorphic zones of the dentate gyrus in treated-mice. Collectively, TASE and thymol could potentially act as natural therapeutic agents for the treatment of neurodegenerative disorders, such as AD.

Thymol as a Potential Neuroprotective Agent: Mechanisms, Efficacy, and Future Prospects

“…92 Thymol and essential oils containing thymol have been shown to improve neurobehavioral changes, including locomotor, attention, learning, and cognitive functions in animal models. 22,24,50,69 Thymol's regulation of neurotransmitters, including DA, NE, 5-HT, GABA, and Ach, contributes to its neuroprotective effects.…”

“…Neurotransmitters play a vital role in nerve cell communication and neurobehavioral functions . Thymol and essential oils containing thymol have been shown to improve neurobehavioral changes, including locomotor, attention, learning, and cognitive functions in animal models. ,,, Thymol’s regulation of neurotransmitters, including DA, NE, 5-HT, GABA, and Ach, contributes to its neuroprotective effects. Thymol has been reported to inhibit acetylcholinesterase (AchE) activity, an enzyme involved in Alzheimer’s disease pathogenesis by hydrolyzing Ach .…”

“…97 Consistently, Timalsina et al found that thymol supplementation at the doses of 50 or 100 mg/kg/day or T. ammi seed extract supplementation (the content of thymol is 33.7%) at the doses of 250 or 500 mg/kg/day (it is equal to thymol at the dose of 84.3 mg/kg/day or 168.5 mg/ kg/day, respectively) could effectively inhibit the production of Aβ 1−42 peptides in the brain tissues of mice. 22 Recent studies also showed that LRP1 also mediates tau internalization and degradation. 98 This evidence indicated that thymol supplementation could reduce the formation of Aβ 1−42 peptides and the hyperphosphorylation of tau via the regulation of the ApoE4/LRP1 axis.…”

“…The ApoE4/LRP1 axis is closely associated with Alzheimer’s disease progression, indicating thymol’s potential to reduce Aβ and Tau pathology through this pathway . Consistently, Timalsina et al found that thymol supplementation at the doses of 50 or 100 mg/kg/day or T. ammi seed extract supplementation (the content of thymol is 33.7%) at the doses of 250 or 500 mg/kg/day (it is equal to thymol at the dose of 84.3 mg/kg/day or 168.5 mg/kg/day, respectively) could effectively inhibit the production of Aβ 1–42 peptides in the brain tissues of mice . Recent studies also showed that LRP1 also mediates tau internalization and degradation .…”

“…Thymol (2-isopropyl-5-methylphenol, Figure ), a naturally occurring monocyclic phenolic compound, is the major active component of the essential oils extracted from several thyme species, including Origanum vulgare , Coridothymus capitatus , and Thymus vulgaris . Many studies from in vitro and animal experiments have demonstrated that thymol possesses potent antioxidant, anti-inflammatory, antimicrobial, and immune-regulation functions. , On the basis of these pharmacological properties, thymol has been widely used in the pharmaceutical field for treating various diseases, including, chronic fibrosis, cancer, immune and inflammatory diseases, cardiovascular disease, infectious disease, and metabolic disease. − Recently, some studies showed that thymol exhibited potential therapeutic effects for several neurological diseases, such as Parkinson’s disease, Alzheimer’s disease, neuro-depression, aging-related learning, and memory impairment. − For example, Javed and colleagues reported that oral thymol supplementation (i.e., 50 mg/kg/day for 28 days) could significantly decrease the biomarkers of oxidative stress, inflammatory response in the brain tissues of rats, following to effectively attenuate neurotoxicity and neurodegeneration caused by rotenone, an inducer of Parkinson’s disease . Similarly, Abu-Elfotuh et al found that oral thymol administration at the final dose of 15 mg/kg/day for 5 weeks (i.e., 35 days) could effectively improve neuronal degeneration and behavioral impairments in rats via the inhibition of oxidative stress, apoptotic cell death, and neuroinflammatory response in the brain tissues of rats with Parkinson’s Disease .…”