NMDAR Down-Regulation: Dual – Hit Molecular Target For COPD – Depression Comorbidity

Abstract

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by sustained airflow limitation that represents one of the main causes of disability in modern society. Depression affects approximately 40% of COPD patients. Both COPD and depression are associated with chronic systemic inflammation and their comorbidity represents a critical unmet treatment need. N-methyl-D-aspartate glutamatergic receptors (NMDAR) are well characterized in the central nervous system (CNS) and widely expressed in lung tissue and inflammation-related cells. Accumulating evidence indicates that pathologic NMDAR up-regulation, leading to pro-inflammatory pathways activation and tissue damage, may play a crucial role in chronic lung injury as well as in depression. D-cycloserine, a bacteriostatic antibiotic used since the 1950’s in tuberculosis, acts at therapeutic dosages also as a NMDAR functional antagonist and has antidepressant and anti-inflammatory effects. We hypothesize that NMDAR down-regulation may represent a unified molecular target for the treatment of COPD – depression comorbidity and may simultaneously alleviate both respiratory and depression symptomatology. We postulate that D-cycloserine treatment may achieve these dual – hit objectives and envisage that our hypotheses may apply to additional inflammation disorders that are frequently accompanied by depression.