Effects on cerebral blood flow after single doses of the β 2 agonist, clenbuterol, in healthy volunteers and patients with mild cognitive impairment or Parkinson's disease

• Published in: British journal of clinical pharmacology Vol. 90; no. 10; pp. 2638 - 2651
• Main Authors: Lodeweyckx, Thomas, de Hoon, Jan, Van Laere, Koen, Bautista, Edgar, Rizzo, Gaia, Bishop, Courtney, Rabiner, Eugenii, Martin, Renee S., Ford, Anthony, Vargas, Gabriel
• Format: Journal Article
• Language: English
• Published: England 01.10.2024
• Subjects: Adrenergic beta-2 Receptor Agonists - administration & dosage; Adrenergic beta-2 Receptor Agonists - adverse effects; Adrenergic beta-2 Receptor Agonists - pharmacology; Adult; Aged; Brain - diagnostic imaging; Brain - drug effects; Brain - metabolism; Cerebrovascular Circulation - drug effects; Clenbuterol - administration & dosage; Clenbuterol - adverse effects; Clenbuterol - pharmacology; Cognitive Dysfunction - chemically induced; Dose-Response Relationship, Drug; Female; Healthy Volunteers; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Nadolol - administration & dosage; Nadolol - adverse effects; Nadolol - pharmacology; Parkinson Disease - drug therapy; Young Adult; clenbuterol; arterial spin labelling MRI; nadolol; neurodegeneration; regional cerebral blood flow; noradrenergic transmission; β‐Adrenoceptor
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.16160

Cerebral hypometabolism occurs years prior to a diagnosis of neurodegenerative diseases and coincides with reduced cerebral perfusion and declining noradrenergic transmission from the locus coeruleus. In pre-clinical models, β-adrenoceptor (β-AR) agonists increase cerebrocortical glucose metabolism, and may have therapeutic potential for neurodegenerative diseases. This study investigated the safety and effects on regional cerebral blood flow (rCBF) of the oral, brain-penetrant β -AR agonist, clenbuterol, in healthy volunteers (HV) and patients with mild cognitive impairment (MCI) or Parkinson's disease (PD). This study evaluated the safety and effects on cerebral activity of the oral, brain-penetrant, β -AR agonist clenbuterol (20-160 μg) in healthy volunteers and patients with MCI or PD. Regional CBF, which is tightly coupled to glucose metabolism, was measured by arterial spin labelling MRI in 32 subjects (25 HV and 8 MCI or PD) across five cohorts. In some cohorts, low doses of nadolol (1-5 mg), a β-AR antagonist with minimal brain penetration, were administered with clenbuterol to control peripheral β -AR responses. Significant, dose-dependent increases in rCBF were seen in multiple brain regions, including hippocampus, amygdala and thalamus, following the administration of clenbuterol to HVs (mean changes from baseline in hippocampal rCBF of -1.7%, 7.3%, 22.9%, 28.4% 3 h after 20, 40, 80 and 160 μg clenbuterol, respectively). In patients with MCI or PD, increases in rCBF following 80 μg clenbuterol were observed both without and with 5 mg nadolol (in hippocampus, 18.6%/13.7% without/with nadolol). Clenbuterol was safe and well-tolerated in all subjects; known side effects of β -agonists, including increased heart rate and tremor, were mild in intensity and were blocked by low-dose nadolol. The effects of clenbuterol on rCBF were evident both in the absence and presence of low-dose nadolol, suggesting central nervous system (CNS) involvement. Concomitant inhibition of the peripheral effects of clenbuterol by nadolol confirms that meaningful β -AR antagonism in the periphery was achieved without interrupting the central effects of clenbuterol on rCBF.