Harrington Discovery Institute Study Leads to Promise for Thirst Disorder Therapeutics
For centuries, the unique, complex structure of the cerebellum, often referred to as the “little brain,” has captivated researchers. Like a well-crafted film or beautifully written book, new details keep emerging even after much study of this evolutionarily ancient part of the brain.
Already linked to motor coordination, thinking, feeling, remembering and feeling full after a meal, the cerebellum also controls thirst. This was the surprising finding of a new study at Harrington Discovery Institute led by Atul Chopra, MD, PhD, Investigator, Harrington Discovery Institute; Associate Director, Harrington Rare Disease Program; and Senior Attending Medical Geneticist, UH Cleveland Medical Center.
Building on previous research focused on hunger and metabolic syndrome, the team’s latest discovery marks a promising start to developing therapies for thirst-related disorders such as polydipsia, suffered by 6% to 20% of psychiatric inpatients and 10% to 20% of all patients with schizophrenia – one-third of whom experience water intoxication requiring hospitalization.
A New Connection
In a recent study, Chopra and his team of researchers from UH, Harrington Discovery Institute and Case Western Reserve University found that a certain hormone helps regulate thirst.
Investigator, Harrington Discovery Institute; Associate Director, Harrington Rare Disease Program; and Senior Attending Medical Geneticist, UH Cleveland Medical Center.
“Asprosin, which we discovered in 2016, was already known for making us feel hungry and keeping our body weight stable by activating important neurons in the brain,” explained Dr. Chopra.
Asprosin connects with a protein receptor called Ptprd that the researchers had previously discovered in the hypothalamus, where the brain controls appetite. Now, they were finding asprosin interacting with the same receptor in the cerebellum, which they thought might be simply helping to coordinate food intake together with the hypothalamus. Then came a breakthrough.
Ila Mishra, PhD, then a postdoctoral fellow on Chopra’s team who now runs a lab at University of Kentucky, made the surprising finding that mice bred to be unresponsive to asprosin in the cerebellum drank less water, but they ate and moved about just the same.
Conversely, mice unresponsive to asprosin in the hypothalamus ate less, but their thirst was unaffected.
The Work Continues: From Discovery to Therapeutic
“Our results show that cerebellar neurons play a role in controlling thirst, separate from their established role in helping us move,” said Dr. Chopra. “It’s amazing that after so many years of studying the brain, we are still finding new functions. This discovery could help us understand and treat thirst disorders like excessive thirst (polydipsia) and low thirst (hypodipsia and adipsia), which currently have no treatments.”
In fact, Chopra and his team have already set out to develop thirst disorder therapeutics – with heartening early results. A drug they made to inhibit asprosin reception in the cerebellum has helped decrease thirst to normal levels in mice with polydipsia.
“We’re now going through all of the steps mandated by the FDA to move this therapeutic toward approval for human use,” said Dr. Chopra.
Ila Mishra, PhD, then a postdoctoral fellow on Chopra’s team who now runs a lab at University of Kentucky, made the surprising finding that mice bred to be unresponsive to asprosin in the cerebellum drank less water, but they ate and moved about just the same