Beta2-Adrenergic Agonists in Treatment for Parkinsonism, with Implications for Neurodegenerative and Neoplastic Disorders

Abstract

AbstractThere is a long record of observations suggesting that β2-adrenergic agonists may have therapeutic value in Parkinson’s disease. Recent studies have focused on the possible role of β2-receptor agonists in suppressing the formation of α-synuclein protein, the component of Lewy bodies. Levalbuterol, the pure levo isomer of the β2 selective agonist, albuterol, has been found to possess significant anti-inflammatory activity, a property that may have the potential to suppress cytokine mediated degeneration of dopaminergic neurons and progression of Parkinsonism. All of the β2 agonist and anti-inflammatory activities of albuterol reside in the levo isomer. The dextro isomer of albuterol substantially negates the efficacies of the levo form. Epinephrine, the prototypical β2 agonist and certain other adrenergic agents, when modeled in the Harvard/MIT Broad Institute genomic database, CLUE, demonstrated strong associations with the gene-expression signatures of drugs possessing glucocorticoid receptor agonist activity. Gene-expression signatures generated by the interaction of the adrenergic drugs of interest in 8 human tumor cell lines were compared with the entire CLUE database of more than 8,000 agents. The signatures were summarized for their consistency (connectivity) across all 8 cell lines and ranked for their relative degree of similarity to the agents in the database. Possible associations with anti-inflammatory activity of glucocorticoids promptedin vivobiological confirmation for levalbuterol and related agonists in the Jackson Laboratory human peripheral blood mononuclear cell (PBMC)-engrafted mouse. Levalbuterol inhibited the release of the eosinophil attractant chemokine, eotaxin-1 (specifically, CCL11), when the mice were challenged with mononuclear antibodies known to provoke cytokine release. Eotaxin is implicated in CNS and peripheral inflammatory disorders. Also, elaboration of the broad tumor-promoting angiogenic factor, VEGFa, and the pro-inflammatory cytokine, IL-13, from activated PBMCs were also inhibited by levalbuterol. These observations suggest possible translation to Parkinson’s disease, other neurodegenerative syndromes, and malignancies, by several mechanisms.