Ischemic stroke is one of the main causes of long-term morbidity/mortality and early treatment of stroke is key issue.
Xenon (Xe) has demonstrated powerful neuroprotective effects on both ischemic and hemorrhagic stroke, but its clinical and long-term outpatient administration is limited by currently available delivery methods. So, development of an oral Xe formulation is an attractive strategy for stroke treatment in the field.
A Xenon (Xe)/alpha-cyclodextrin (aCD) complex containing oral formulation was developed. It was hypothesized that efficient oral xenon gas delievery by Xe/aCD formulation as a treatment will reduce the severity of brain infarct and reduce arterial occlusion in acute experimental stroke. (1)
A stable, oral Xe-aCD clathrate complex (Xe solid gas) was formed by pressurizing Xe gas at 3 atm into a 14 % alpha-cyclodextrin aqueous solution at room temperature. Xe load and concentration was measured by GC-MS.
Rat Middle Cerebral Artery Occlusion (MCAO) was induced by intraluminar suture. The animals were divided into groups:
- stroke (n=4);
- stroke with aCD (n=3);
- stroke with 0.5 ml Xe-aCD (n=3);
- stroke with 1.0 ml Xe-aCD (n=3); and
- stroke with 1.5 ml Xe-aCD (n=3).
Treatments were administered by oral gavage once a day for 3 days. At day 3, neurological behavior testing was conducted. The brain infarct size and neuronal death were assessed and normalized by total brain volume.
The results were promising: The MCAO for 2 hours induced 21% ± 3.6% infarct volume. Xe-aCD treatment dose-dependently reduced the infarct size to 18.9% ± 2.3% by 0.5 ml Xe-CD, 6.7% ± 1.8% by 1.0 ml Xe-CD, and 4.8% ± 1.2% by 1.5 ml Xe-CD (see Figure 1 A below). Behavioral test assessment using forelimb placement rate and Rotarod score matched infarct size. TUNEL staining demonstrated significant decreases in apoptosis in stroke rats treated with 1.5 ml Xe-CD (see Figure 1 B below).
This study has demonstrated that oral Xe-alphaCD formulation ameliorates neuronal apoptosis and reduces infarct size. Xe-alphaCD complex represents a promising therapeutic for ischemic stroke treatment.
It is interesting to see that more than 60 years after the publication of the seminal paper by Cramer and Henglein on the inclusion complexes of noble gases with alpha-CD (2), some real clinical/therapeutic applications of these complexes are recognized.
One of the early report on the therapeutic application of noble gase cyclodextrin inclusion complexes was described in a British patent application, in 2002. (3) The patent disclosed an infusion formulation for inducing and/or maintaining anesthesia includes a complex of a noble gas, i.e., krypton or xenon, and a molecular encapsulating agent. The latter is a CD, its derivative, a soluble polymer or a rotaxane. The formulation may also be used as an analgesic formulation or in a neuroprotective formulation.
(1) Reference: Xing Yin, et al : Oral Xe-Cyclodextrin Provides Neuroprotection for Ischemic Stroke Treatment published30 Oct 2022, Circulation. 2022; 146: A12601, https://www.ahajournals.org/doi/abs/10.1161/circ.146.suppl_1.12601
(2) Cramer, F. Henglein, F. M. Inclusion Compounds XII. Complexes of Alpha-Cyclodextrin with gases. Chem. Ber. 90 2572, 1957.
(3) Mason, Rodney Stewart; Moozyckine, Alexei Uriah; Dingley, John, Noble gas complexes. PCT Int. Appl. WO 2002045721 A1 13 Jun 2002, 23 pp.