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

Abstract

There is a long record of observations suggesting that {beta}2-adrenergic agonists may have therapeutic value in Parkinsons disease. Recent studies have focused on the possible role of {beta}2-receptor agonists in suppressing the formation of -synuclein protein, the component of Lewy bodies. Levalbuterol, the pure levo isomer of the {beta}2 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 the {beta}2 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 {beta}2 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 prompted in vivo biological 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 Parkinsons disease, other neurodegenerative syndromes, and malignancies, by several mechanisms.