Andreas Raschig

Treatment with the selective muscarinic ml agonist talsaclidine decreases cerebrospinal fluid levels of Aβ42 in patients with Alzheimer's disease

The amyloid p-peptides Aβ40 and Aβ42 are highly amyloidogenic constituents of brain Pamyloid plaques in Alzheimers disease (AD). Lowering their formation may be achieved by modulating the activities of proteases that cleave the amyloid precursor protein (AβPP), including α-β-, and γ-secretases. Talsaclidine is a functionally selective muscarinic ml agonist that stimulates non-amyloidogenic a-secretase processing in vitro. We compared cerebrospinal fluid (CSF) levels of Aβ40 and Aβ42 measured by ELISA before and at the end of 4 weeks of treatment with talsaclidine. The medication was administered in a double- blind, placebo-controlled, and randomized clinical study to 40 patients with AD. Talsaclidine (n=34) decreased CSF levels of Aβ42 by a median of 19% (p < 0.001) as compared to baseline. The mean diflerence between CSF levels of Aβ42 before and after treatment with talsaclidine (n=34) was -46.73 (SD) pg/ml as compared to 0.8 (SD)pg/ml with placebo (n=6) (p < 0.05). CSF levels of Aβ40 increased during treatement with placebo (n=6) while they remained stable during treatment with talsaclidine (n=31) (1.118±1.710 ng/ ml, and-0.170A0.967 ng/ml, respectively; p < 0.05). These data show that treatment with the ml agonist talsaclidine reduced Aβ peptides, and particularly Aβ42, in AD patients, suggesting it as a potential amyloid lowering therapy of AD.

Treatment with the Selective Muscarinic Agonist Talsaclidine Decreases Cerebrospinal Fluid Levels of Total Amyloid β‐Peptide in Patients with Alzheimer's Disease

Abstract: Brain amyloid load in Alzheimers disease (AD) is, at least in genetic forms, associated with overproduction of amyloid β‐peptides (Aβ). Thus, lowering Aβ production is a central therapeutic target in AD and may be achieved by modulating such key enzymes of amyloid precursor protein (APP) processing as β‐, γ‐, and α‐secretase activities. Talsaclidine is a selective muscarinic M1 agonist that stimulates the nonamyloidogenic α‐secretase pathway in model systems. Talsaclidine was administered double‐blind, placebo‐controlled, and randomized to 24 AD patients and cerebrospinal fluid (CSF) levels of total Aβ were quantitated before and after 4 weeks of drug treatment. We observed that talsaclidine decreases CSF levels of Aβ significantly over time within the treatment group (n=20) by a median of 16% as well as compared to placebo (n=4) by a median of 27%. We conclude that treatment with selective M1 agonists may reduce Aβ production and may thus be further evaluated as a potential amyloid‐lowering therapy of AD.

Pharmacodynamic profile of the M1 agonist talsaclidine in animals and man

In functional pharmacological assays, talsaclidine has been described as a functionally preferential M1 agonist with full intrinsic activity, and less pronounced effects at M2- and M3 receptors. In accordance with this, cholinomimetic central activation measured in rabbits by EEG recordings occurred at a 10 fold lower dose than that inducing predominantly M3-mediated side effects. This pharmacological profile is also reflected in the clinical situation: Both in healthy volunteers and in Alzheimer patients--unlike after unspecific receptor stimulation through cholinesterase inhibitors--the mainly M3-mediated gastrointestinal effects (like nausea and vomiting) were not dose-limiting. Rather, sweating and hypersalivation, mediated through muscarinic receptors, occurred dose-dependently and were finally dose-limiting. In contrast to talsaclidine, sabcomeline had a less pronounced functional M1 selectivity in pharmacological assays. This was also shown in anaesthetized guinea pigs where sabcomeline alone induced bronchoconstriction, and in the rabbit EEG where central activation and cholinergic side effects occurred in the same dose range. Neither drug, however, showed convincing improvement of cognitive functions in patients with mild-to-moderate Alzheimers disease. This asks for a reassessment of the muscarinic hypothesis for the treatment of this disease.