On 15 August, 2024 Douglas Kelley, professor of mechanical engineering at the University of Rochester and his co-workers published that a long-used and known drug active appears to restart the flow of brain-cleaning fluids, and restores the brain’s trash disposal system. (1)
Some neurological disorders, like Alzheimer’s, Parkinson’s diseases can be regarded as “dirty brain” diseases, where the brain stops to clear out its harmful “waste”. Aging is a high-risk factor because, as we get older, our brain’s ability to remove toxic “waste” slows down.
However, this new research done on mice demonstrates that it seems possible to restore the brain’s waste-clearing process. The encouraging results of this study were accomplished with a drug already being used clinically, so offering a potential treatment strategy. (This could be another drug repositioning example, provided that these results will be sufficiently corroborated.)
The glymphatic system:
It was in 2012 first described by M. Nedergaard (also co-author of this Nature Aging paper), that the so-called glymphatic system in the brain is responsible for waste removal process. (2)
This system uses cerebrospinal fluid to wash away excess proteins generated by energy-hungry neurons and other cells in the brain during its normal function. In healthy and young brains, the glymphatic system works well and flushes away the toxic waste proteins; but, as we age, this system slows down, resulting in some neurological disorders. Anatomically, a network of “microscopic pumps” removes the waste from the brain. Once brain gets full with protein waste, cerebrospinal fluid needs to make its way to the lymphatic system and, ultimately, to the kidneys, where the waste is processed together with other wastes of the body. The results of this study pointed the way to potential new approaches to treat diseases commonly associated with the accumulation of protein waste in the brain, such as Alzheimer’s (beta amyloid and tau) and Parkinson’s (alpha-synuclein).
The new research combines advanced imaging and particle-tracking techniques to describe for the first time in detail the route by way of the cervical lymph vessels in the neck through which half of dirty cerebrospinal fluid exits the brain. In addition to measuring the flow of cerebrospinal fluid, the researcher team was able to observe and record the pulsing of lymph vessels in the neck that helps draw cerebrospinal fluid out of the brain.
The researchers found that as the mice aged, the frequency of contractions decreased, and the valves failed. As a result, the speed of dirty cerebrospinal fluid flowing out of the brains of older mice was 63 % slower compared to young animals.
The known drug identified:
The team identified a drug, called prostaglandin F2α, a hormone-like, naturally occurring unique fatty acid derivative, that is commonly used in human and veterinary therapy to induce labor. (This API is highly potent to cause smooth muscle contraction.)
The lymphangions of the brain are lined with smooth muscle cells, and when the researchers applied prostaglandin F2α to the cervical lymph vessels in older mice, the frequency of contractions and the flow of dirty cerebrospinal fluid from the brain both increased, returning to a level of efficiency typical in young mice.
The results of this new observation, perhaps combined with other interventions, could serve the basis for future therapies for the age-related neurological diseases.
Prostaglandin F2α and Cyclodextrins:
Cyclodextrin researchers are familiar with the interaction between cyclodextrins and prostaglandins. It has long been known that parent alpha-, beta- and gamma-cyclodextrins as well s CD-derivatives can be used to stabilize, solubilize these lipophilic, sensitive fatty acid derivatives of high physiological potency.
It is also noteworthy that there are some approved and marketed cyclodextrin-based prostaglandins. ( for example PGE1 with alpha-CD as Prostavasin and PGE2 with beta-CD as Prostarmon are marketed) Interestingly, prostaglandin F2α was not developed on cyclodextrin excipient basis, though Professor Uekama’s team published on gamma-CD complexes of prostaglandin F2α. They found that solid complex of prostaglandin F2α (dinoprost) with gamma-cyclodextrin formed in a molar ratio of 1:1 The mode of interaction in the solid state was also studied by using powder X-ray diffractometry, thermal analysis, and carbon-13 cross polarization/magic angle spinning nuclear magnetic resonance solid state NMR. The X-ray and NMR data suggested that prostaglandin F2α is included in the cylindrical channels formed by coaxial alignment of gamma-cyclodextrin molecules to give a channel type structure. Dissolution and thermal behavior of the prostaglandin F2α -gamma-cyclodextrin complex were examined and compared with the drug itself. It was concluded that the gamma-cyclodextrin complex may have great utility as a rapidly dissolving form of prostaglandin F2α with improved thermal stability. (3)
Therefore, some cyclodextrin-enabled, highly water-soluble prostaglandin F2α formulations could be considered in this respect as a possible therapeutic approach for neurodegenerative disorders.
References
1. Du, T., Raghunandan, A., Mestre, H. et al. Restoration of cervical lymphatic vessel function in aging rescues cerebrospinal fluid drainage. Nat Aging (2024). https://doi.org/10.1038/s43587-024-00691-3Nature
2. Hablitz, L. and Nedergaard,M. The glymphhatic system : A Novel Component of Fundamental Neurobiology J. Neurosci. 2021 Sept. 15. v41. 37.m 7698-7711.
3. K Uekama, F Hirayama, A Fujise, M Otagiri, K Inaba, H Saitô. Inclusion complexation of prostaglandin F2 alpha with gamma-cyclodextrin in solution and solid phases a Prostglandin J Pharm Sci 1984 Mar;73(3):382-4. doi: 10.1002/jps.2600730323.