Alzheimer’s disease (AD) is one of the most prevalent dementia, characterized by irreversible and progressive cognitive dysfunction. Senile plaques, also known as amyloid plaques which are composed of insoluble and aggregative peptides, e.g. β-amyloid protein (Aβ), are well recognized as the pathogenesis of AD. These self-assembly peptide aggregates produce extracellular deposition or smaller soluble oligomer species, recognized as the amyloid cascade hypothesis or oligomer hypothesis, respectively. In addition to these two well-accepted theories, recently, metal dyshomeostasis has unquestionably gained much attention. Substantial quantities of metal ions, including Cu2+, Fe3+ and Zn2+, are found in the core and periphery of plaque formations in the brains of AD patients. Among them, Cu2+ is generally believed to play a role in two pathways relevant to the pathophysiology of AD. Thus, it is urgent to develop multifunctional agents targeting multiple pathologies of AD, not just for inhibition of Aβ aggregation or chelation of excess Cu2+, but also for scavenging ROS and anti-neuroinflammation. [1] multifunctional chiral carbon dots based on ternary carbon sources, L/d-cysteine, β-cyclodextrin and citric acid, were designed and prepared. β-cyclodextrin played important multiple roles to induce chirality, enhance Cu2+ binding ability, and promote the antioxidant ability. [2]
The effect of 2-hydroxypropyl-β-cyclodextrin (HPBCD) on cholesterol, oxidative stress (total oxidant status), neuroinflammation (TNF-α), and mGluR5 signaling molecules such as PKCβ1, PKCβ2, ERK1/2, CREB, BDNF, and NGF in Aβ (1-42)-induced neurotoxicity was studied. The Sprague-Dawley rats were divided into four groups: control (saline), Aβ (1-42), HPBCD (100 mg/kg), and Aβ (1-42) + HPBCD (100 mg/kg). All groups received bilateral stereotaxic injections of Aβ (1–42) or saline into the hippocampus. After surgery, HP-CD was administered intraperitoneally (ip) for 7 days. Cholesterol, TNF-α, and TOS levels were measured in synaptosomes isolated from hippocampus tissue using spectrophotometry, fluorometry, and enzyme immunoassay, respectively. Treatment with Aβ (1-42) significantly elevated cholesterol, TOS, TNF-α, Cav-1, PKCβ2, and ERK1/2 levels. Additionally, mGluR5, CREB, and BDNF levels were shown to be lowered. HP-CD reduced cholesterol, TOS, and TNF-α levels while increasing mGluR5, CREB, and BDNF in response to Aβ (1–42) treatment. These findings indicate that HPBCD as a drug may have neuroprotective activity due to the decreased levels of cholesterol, oxidative stress, and neuroinflammation, as well as upregulated levels of mGluR5, CREB, and BDNF. [3]
Various small molecules complexed with CD are also in the focus of research. Some recent examples:
- Natural oxyresveratrol-β-cyclodextrin (ORV-CD) reversed the cognitive-behavioural deficit and prominently reduced the MDA and histone deacetylase-2 levels comparable to the effect of the standard drug, donepezil. The findings suggest anti-Alzheimner disease role of ORV-CD via antioxidant effect and inhibition of histone deacetylase-2 in the hippocampal and frontal cortical area of rats in Alzheimner disease. [4]
- The antioxidant and anti-Aβ1–42 aggregation properties of 1,8-cineole (in other name eucaliptol, an ingredient of several essential oils) were enhanced in C. elegans when used as a β-cyclodextrin inclusion complex [5].
- Ginsenoside F1 (GF1) is a potential drug candidate for the treatment of Alzheimer’s disease. HP-β-CD inclusion complex improved GF1 solubility by 150 fold. Following intranasal delivery, the absolute bioavailability of inclusion complex was 46%, with drug brain targeting index (DTI) 247% and nose-to-brain direct transport percentage (DTP) 58%.[6]
[1] M. Rana, A.K. Sharma, Cu and Zn interactions with Aβ peptides: consequence of coordination on aggregation and formation of neurotoxic soluble Aβ oligomers. Metallomics, 11 (1) (2019), 64-84. https://doi.org/10.1039/c8mt00203g
[2] Lina Bao, Wanchun Luo, et al., Chiral carbon dots based on ternary carbon sources: A multifunctional therapeutic agent for Cu2+-induced Alzheimer’s disease. Carbon 228 (2024) 119333,
https://doi.org/10.1016/j.carbon.2024.119333.
[3] Yalcin, A., Turunc, E., et al. Potential neuroprotective effects of 2-hydroxypropyl-β cyclodextrin against amyloid β (1-42)-induced neurotoxicity on the rat hippocampus. Drug and Chemical Toxicology (2024) 1–8. https://doi.org/10.1080/01480545.2024.2349951
[4] Agarwal, T., Manandhar, S., B, H.K. et al. Oxyresveratrol-β-cyclodextrin mitigates streptozotocin-induced Alzheimer’s model cognitive impairment, histone deacetylase activity in rats: in silico & in vivo studies. Sci Rep 14, 9897 (2024). https://doi.org/10.1038/s41598-024-57188-7
[5] Xin Tan, Rui Xu, et al. Antioxidant and anti-Alzheimer’s disease activities of 1,8-cineole and its cyclodextrin inclusion complex, Biomedicine & Pharmacotherapy 175 (2024) 116784.
https://doi.org/10.1016/j.biopha.2024.116784.
[6] Ying Mao, Weihua Yuan, et al. Enhanced brain distribution of Ginsenoside F1 via intranasal administration in combination with absorption enhancers. International Journal of Pharmaceutics 654 (2024 ) 123930. https://doi.org/10.1016/j.ijpharm.2024.123930