Present anti-PD and -AD drugs have limited symptomatic activity and devoid of neuroprotective and neurorestorative property that is needed for disease modifying action. The complex pathology of PD and AD led us to develop several multi-target neuroprotective and neurorestorative drugs with several CNS targets with the ability for possible disease modifying activity. Employing the pharmacophore of our anti-parkinson
drug rasagiline (Azilect, N-propagrgyl-1-R-aminoindan), we have developed a series of novel multi-functional
neuroprotective drugs (A) [
TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate)], with both
cholinesterase-
butyrylesterase and brain selective
monoamine-oxidase (
MAO) A/B inhibitory activities and (B) the
iron chelator-radical scavenging-brain selective
monoamine oxidase (
MAO) A/B inhibitor and M30 possessing the neuroprotective and neurorescuing propargyl moiety of
rasagiline, as potential treatment of AD, DLB and PD with
dementia. Another series of multi-target drugs (M30, HLA-20 series) which are brain permeable
iron chelators and potent selective brain
MAO inhibitors were also developed. These series of drugs have the ability of regulating and processing
amyloid precursor
protein (APP) since APP and
alpha-synuclein are metaloproteins (
iron-regulated
proteins), with an
iron responsive
element 5"UTR mRNA similar to transferring and
ferritin.
Ladostigil inhibits brain acetyl and
butyrylcholinesterase in rats after oral doses. After chronic but not acute treatment, it inhibits
MAO-A and -B in the brain.
Ladostigil acts like an anti-depressant in the forced swim test in rats, indicating a potential for anti-depressant activity.
Ladostigil prevents the destruction of nigrostriatal neurons induced by infusion of
neurotoxin MPTP in mice. The
propargylamine moiety of
ladostigil confers neuroprotective activity against cytotoxicity induced by
ischemia and
peroxynitrite in cultured neuronal cells. The multi-target
iron chelator M30 has all the properties of
ladostigil and similar neuroprotective activity to
ladostigil, but is not a ChE inhibitor. M30 has a neurorestorative activity in post-lesion of nigrostriatal dopamine neurons in
MPTP, lacatcystin and
6-hydroxydopamine animal models of PD. The neurorestorative activity is related to the ability of the
drug to activate
hypoxia inducing factor (HIF) which induces the production of such
neurotrophins as
brain-derived neurotrophic factor (
BDNF),
vascular endothelial growth factor (
VEGF) and
erythropoietin as well as glia-derived
neurotrophic factor (
GDNF). The unique multiple actions of
ladostigil and M30 make the potentially useful drugs for the treatment of
dementia with Parkinsonian-like symptoms and depression.