Jean-Paul Kan

Administration of amyloid β-peptides in the rat medial septum causes memory deficits: reversal by SR 57746A, a non-peptide neurotrophic compound

Different putative toxic amyloid beta (A beta) peptides, beta (1-42), beta (1-40) and beta (25-35), were infused (0.75, 1.5 or 3 nmol) in the rat medial septum. Memory deficits were then investigated using the social recognition test. A significant amnesia was observed 4, 7 and 14 days after intraseptal injection of 3 nmol of beta (1-42), beta-(1-40)- and beta (25-35). Lower amounts of beta (1-42) were inactive except 1.5 nmol that disrupted memory 7 days post-treatment. Used as control, the inverted peptide beta (40-1) and the scrambled beta (25-35) were inactive. Using the prolongation procedure, rats infused with 3 nmol of beta (1-40) were still able to recognize the same juvenile. Finally, a daily treatment with the non-peptide neurotrophic compound SR 57746A (10 mg/kg p.o.) over 21 days, prevented the deficits in short-term memory induced by the intraseptal infusion of 3 nmol of either beta (1-40) or beta (25-35). These findings suggest that A beta fragments could impair short-term memory when infused in the rat medial septum, an effect that is prevented by SR 57746A.

SR 46559 A and related aminopyridazines are potent muscarinic agonists with no cholinergic syndrome

The development of an aminopyridazine lead structure (minaprine) yielded compound SR 46559 A 3-[N-(2-diethyl-amino-2-methylpropyl)-6-phenyl-5-propyl] pyridazinamine sesquifumarate, a novel and potent muscarinic agonist with no cholinergic syndrome.

SR 46559A: a novel and potent muscarinic compound with no cholinergic syndrome

The cholinergic activities of SR 46559A, 3-[N-(2 diethyl-amino-2-methylpropyl)-6-phenyl-5-propyl] pyridazinamine sesquifumarate, have been investigated in vitro and in vivo, in rodents. Using rat brain cortical membranes, SR 46559A was a competitive ligand (Ki=112 nM) at muscarinic M1 receptors, its affinity for muscarinic M2 (cardiac) and M3 (glandular) receptors being 6–7 times lower. SR 46559A did not interact with brain nicotinic receptors and high affinity choline uptake sites nor did it inhibit brain acetylcholinesterase activity. In contrast to reference muscarinic agonists, SR 46559A (1 mM) did not inhibit the forskolin-induced activation of cAMP synthesis nor did it stimulate phosphoinositides breakdown in various brain preparations. However, this compound enhanced (+67% at 1 mM) diacylglycerol formation in rat striatal miniprisms, an effect fully reversed by atropine. As shown with reference agonists, SR 46559A inhibited (IC50=10 µM) the K+-evoked release of [3H]GABA from rat striatal slices and reduced at 0.5 and 1 µM, the population spike amplitude of the CA1 pyramidal cells induced by stimulation of the Schaffers collateral commissural pathway in rat hippocampal slices. In mice, SR 46559A at a near lethal dose (200 mg/kg PO) did not induce the typical cholinergic syndrome nor did it modify at 30 mg/kg PO the oxotremorine-induced hypothermia. Like muscarinic agonists, SR 46559A (1 mg/kg PO) potentiated haloperidol-induced catalepsy in rats and inhibited (ED50=0.12 mg/kg PO) rotations induced in mice by intrastriatal injection of pirenzepine. SR 46559A prevented the scopolamine- or pirenzepine-induced deficit in passive avoidance learning, this compound being 3 times more potent on pirenzepine-induced amnesia. Moreover, using the social memory test, SR 46559A (0.1–3 mg/kg PO) enhanced short-term retention in adult rats and improved memory deficits observed in aged mice and in rats subjected to cerebral ischeamic insult. SR 46559A (1–3 mg/kg PO) also reversed the ischaemia-induced alterations of rats exploratory behaviour. Taken together, these results suggest that SR 46559A behaves as an atypical muscarinic compound which, at least in part, could stimulate muscarinic receptors coupled to phosphatidylcholine/phospholipases C or D signalling pathways. This drug has a marked ability to improve experimentally induced cognitive deficits in rodents without producing cholinergic symptomatology. Thus, SR 46559A could be a potential useful drug for the symptomatic treatment of Alzheimers disease.