Exp Neurobiol.  2013 Mar;22(1):1-10. 10.5607/en.2013.22.1.1.

Multi Target Neuroprotective and Neurorestorative Anti-Parkinson and Anti-Alzheimer Drugs Ladostigil and M30 Derived from Rasagiline

• Youdim MB

• KMID: 2165435
• DOI: http://doi.org/10.5607/en.2013.22.1.1

Abstract

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.

Keyword

brain selective MAO inhibition; multi-target drugs; neuroprotective and neurorestorative drugs; antidepressant activity

MeSH Terms

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
alpha-Synuclein
Amyloid
Animals
Anoxia
Brain
Brain-Derived Neurotrophic Factor
Butyrylcholinesterase
Chelating Agents
Dementia
Depression
Dopamine
Erythropoietin
Ferritins
Indans
Iron
Ischemia
Mice
Models, Animal
Monoamine Oxidase
Monoamine Oxidase Inhibitors
Nerve Growth Factors
Neurons
Neuroprotective Agents
Oxidopamine
Pargyline
Peroxynitrous Acid
Propylamines
Rats
RNA, Messenger
Vascular Endothelial Growth Factor A
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Amyloid
Brain-Derived Neurotrophic Factor
Butyrylcholinesterase
Chelating Agents
Dopamine
Erythropoietin
Ferritins
Indans
Iron
Monoamine Oxidase
Monoamine Oxidase Inhibitors
Nerve Growth Factors
Neuroprotective Agents
Oxidopamine
Pargyline
Peroxynitrous Acid
Propylamines
RNA, Messenger
Vascular Endothelial Growth Factor A
alpha-Synuclein