During the past decade, much attention has been focused on possible “neuroprotective” effects of presently available antidementia drugs. Neuroprotection includes a wide range of aspects, from protection against the action of neurotoxins on neuroreceptors, through inhibition of apoptosis and recovery of a normal metabolic state of cells, to synaptic and neuronal sprouting, formation, removal and stabilization of synaptic contacts and genesis of new brain cells. Galantamine has been shown in in-vitro and in animal models to be capable of inducing a variety of such neuroprotective effects. Based on these data, a pathology cascade can be envisaged, with galantamine-induced sensitization of nicotinic receptors beneficially interfering at the levels of nAChR inhibition by Aß, nAChR-induced loss of function in other transmitter systems, nAChR loss, and apoptosis.
Most of the studied neuroprotective effects of galantamine seem to be mediated by α7 nAChR, the subtype that has the highest Ca2+ permeability of all nicotinic receptors and seems to be associated with many modulatory activities in the CNS. Interestingly, activation of this receptor may also affect neurogenic vasodilation, with perivascular sympathetic nerve Ca2+ influx leading to noradrenalin release, subsequent ß-adrenoreceptor activation and NO release. These findings suggest a link between the nAChR deficit in AD and cerebrovascular risk factors of AD.
Present drugs are far from being a fully satisfactory treatment for AD, as all present drugs do not halt or reverse the progression of neurodegeneration to any significant extent. Nicotinic APL therapy has shown some promise in this regard, both in animal model studies and in long-term open-label studies. GalantosPharma is actively pursuing research to fully unveil the potential of this therapy by developing drugs with optimized neuroprotective properties.
At the present stage of our drug development program, we have identified several lead structures that competitively reduce the inhibition of nicotinic receptors by ß-amyloid peptides. The same lead structures are also capable of reducing in transgenic animal models of AD the ß-amyloid load developing in these animals after birth, and of activating de novo synthesis of brain cells. Memogain is one of our drug candidates displaying these properties already at rather low dose and with high potency.