PMID- 23585716
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20130416
LR  - 20211021
IS  - 1226-2560 (Print)
IS  - 2093-8144 (Electronic)
IS  - 1226-2560 (Linking)
VI  - 22
IP  - 1
DP  - 2013 Mar
TI  - Multi target neuroprotective and neurorestorative anti-Parkinson and 
      anti-Alzheimer drugs ladostigil and m30 derived from rasagiline.
PG  - 1-10
LID - 10.5607/en.2013.22.1.1 [doi]
AB  - 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.
FAU - Youdim, Moussa B H
AU  - Youdim MB
AD  - Technion Rappaort Faculty of Medicine, Eve Topf and NPF Centers of Excellence for 
      Neurodegenerative Diseases Haifa, Haifa 30196, Israel. ; Department of Systems 
      Biology, Yonsei University, Seoul 120-749, Korea.
LA  - eng
PT  - Journal Article
DEP - 20130331
PL  - Korea (South)
TA  - Exp Neurobiol
JT  - Experimental neurobiology
JID - 101278187
PMC - PMC3620452
OTO - NOTNLM
OT  - antidepressant activity
OT  - brain selective MAO inhibition
OT  - multi-target drugs
OT  - neuroprotective and neurorestorative drugs
EDAT- 2013/04/16 06:00
MHDA- 2013/04/16 06:01
PMCR- 2013/03/01
CRDT- 2013/04/16 06:00
PHST- 2013/03/01 00:00 [received]
PHST- 2013/03/04 00:00 [revised]
PHST- 2013/03/04 00:00 [accepted]
PHST- 2013/04/16 06:00 [entrez]
PHST- 2013/04/16 06:00 [pubmed]
PHST- 2013/04/16 06:01 [medline]
PHST- 2013/03/01 00:00 [pmc-release]
AID - 10.5607/en.2013.22.1.1 [doi]
PST - ppublish
SO  - Exp Neurobiol. 2013 Mar;22(1):1-10. doi: 10.5607/en.2013.22.1.1. Epub 2013 Mar 
      31.