Evaluation of Chorionic Gonadotropin as a Treatment for Sepsis-induced Neuroinflammation and Cognitive Dysfunction in the Aged Brain
Name:
Dr. Gemma Casadesus
Email
gcasadesus@ufl.edu
Phone
(352) 294-5346
Faculty Department/Division
Pharmacology
This project is primarily:
Basic
Research Project Description:
Seventy percent of sepsis patients show some degree of acute diffuse neurological impairment. Importantly about half show chronic neurocognitive impairments, ten percent of which are noted to be severe. In older individuals the incidence of sepsis is significantly higher as is the risk of long-term severe cognitive impairment. Given the rapidly increasing numbers of aged individuals and the significant economic and functional burden that this poses to the individual and the families of these patients, identifying neuroprotective therapies to prevent long-term changes in the brains of sepsis patients is of high significance to the field. This is particularly important since increasing data suggests a strong link between sepsis and later development of dementia, an aspect that is recapitulated in rodent AD models, were sepsis increases pathology associated with this disease. However, despite the high incidence and clinical relevance of neurological disturbances during and after sepsis, the pathological mechanisms underlying both acute and chronic neurological dysfunction are not fully understood. To date, there are no effective therapies to treat or mitigate these long-term sequalae.
A key emerging mechanism linking sepsis to cognitive impairment involves immune cell infiltration into the CNS secondary to blood brain barrier dysfunction during the acute phase of the infection. To this end, we have identified that the luteinizing hormone receptor agonist, hCG, which we have previously shown to protect cognition in aging menopausal and AD mouse models, has powerful anti-inflammatory effects within the brain. These are in line with the expression of this receptor by microglia and excitatory neurons in the brain but also parallel the established role for this hormone in the periphery where, during pregnancy, it is a major regulator of key immune cells (i.e. neutrophils and monocytes) that are known to infiltrate and cause cognitive dysfunction in sepsis models. Therefore, we seek to address whether 1) hCG will prevent long-term cognitive dysfunction associated with sepsis in aged mice and 2) whether these benefits are associated with the regulation of peripheral cell infiltration and/or centrally mediated pro-inflammatory mechanisms. Notably, given the involvement of this inflammatory mechanism in other neurological disorders (TBI, neurogenerative disorders, stroke) the mechanistic evaluation of LHCGR agonists can be readily generalizable to other CNS conditions that impact the aged brain.
Does this project have an international component or travel?
No