Corticotrophin releasing factor receptor 1 antagonists prevent chronic stress-induced behavioral changes and synapse loss in aged rats

Abstract

Mounting evidence suggests that chronic stress can alter brain structure and function and promote the development of neuropsychiatric disorders, such as depression and Alzheimer's disease. Although the results of several studies have indicated that aged brains are more vulnerable to chronic stress, it remains unknown whether antagonists of a key stress regulator, the corticotrophin releasing factor receptor 1 (CRF1), can prevent stress-induced anxiety and memory deficits in animal models. In this study, we evaluated the potential benefits of two CRF1 antagonists, R121919 and antalarmin, for preventing stress-induced anxiety-related behavioral and memory deficits and neurodegeneration in aged rats. We stressed rats using isolation-restraint for 3 months starting from the 18 months of age. Subsets of animals were administrated either R121919 or antalarmin through food chow for 3 months, followed by a series of behavioral, biochemical and morphological analyses. We found that stressed aged rats displayed body weight losses and increased corticosterone levels, as well as anxiety-related behaviors and memory deficits. Additionally, chronic stress induced a loss of cortical dendritic spines and synapses. However, R121919 and antalarmin both prevented stress-induced behavioral changes including anxiety-related behaviors and memory deficits and prevented synapse loss, perhaps through reversing HPA axis dysfunction. These results suggest that CRF1 antagonists may hold promise as a potential therapy for preventing stress-induced anxiety and memory deficits in aged individuals.

Chronic Stress Induces Maladaptive Behaviors by Activating Corticotropin-Releasing Hormone Signaling in the Mouse Oval Bed Nucleus of the Stria Terminalis

“…Our results showing that the infusion of the CRHR1-selective antagonist R121919 into ovBNST can reverse maladaptive behaviors (Fig. 4) is therefore consistent with several reports testing systemic effects of CRH modulators (Heinrichs et al, 2002;Gutman et al, 2003;Micioni Di Bonaventura et al, 2014;Dong et al, 2018).…”

Is AD a Stress-Related Disorder? Focus on the HPA Axis and Its Promising Therapeutic Targets

“…These authors also showed that chronic administration of antalarmin ( a CRH-R1 antagonist ) significantly decreased plasma corticosterone levels, tissue Aβ 1–42 levels and Aβ plaques deposition in the brain, and blocked the effects of isolation stress on anxiety levels and memory (Dong et al, 2014). A few years later, a 3 month-treatment in food with CRH-R1 antagonists ( Antalarmin and R121919 ) was shown to prevent stress-induced behavioral changes ( anxiety and memory ) and synaptic loss in aged rats, perhaps by reversing HPA axis dysfunction (Dong et al, 2018). Moreover, in another mouse model of AD ( APP/PS1 ) a 5 month-treatment with R121919 prevented the onset of cognitive impairment, reduced cellular and synaptic deficits and Aβ levels (Zhang et al, 2016).…”

Role of Corticotropin Releasing Factor in the Neuroimmune Mechanisms of Depression: Examination of Current Pharmaceutical and Herbal Therapies

“…For example, potential clinical applications of CRF1 receptor antagonists include the treatment of anxiety, allergy, autoimmune inflammatory disorders, epilepsy and so on (Grammatopoulos and Chrousos, 2002). In aged rats, two CRF1 receptor antagonists, R121919 and antalarmin, prevented chronic stress-induced anxiety-related behavioral and memory deficits (Dong et al, 2018). Although CRF1 receptor antagonists show promising effects in rodents, their clinical efficacy is mixed.…”