Author: Trkulja, Vladimir ; Osmanovic-Barilar, Jelena ; Salkovic-Petrisic, Melita ; Amit, Tamar ; Mandel, Silvia ; Knezovic, Ana ; Smailovic, Una ; Youdim, Moussa B H ; Riederer, Peter

AIMNovel effective treatment is urgently needed for sporadic Alzheimer's disease (sAD). M30 ([5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline]) and HLA-20 (5-{4-propargylpiperazin-1-ylmethyl}-8-hydroxyquinoline) are brain permeable, iron chelating compounds with antioxidant activity, showing also neuroprotective activity in animal models of neurodegeneration.Weaimed to explore their therapeutic potential in non-transgenic (non-Tg) rat model of sAD developed by intracerebroventricular administration of streptozotocin (STZ-icv).MAIN METHODSTherapeutic effects of chronic oral M30 (2 and 10 mg/kg) and HLA20 (5 and 10 mg/kg) treatment on cognitive impairment in STZ-icv rat model were explored by Morris Water Maze (MWM) and Passive Avoidance (PA) tests in neuropreventive and neurorescue paradigms. Data were analysed by Kruskal–Wallis and Mann–Whitney U test (p b 0.05).KEY FINDINGSFive-day oral pre-treatment with M30 and HLA20 dose-dependently prevented development of spatial memory impairment (MWM probe trial-time +116%/M30; +60%/HLA20) in STZ-icv rat model (p b 0.05). Eleven-week oral treatment with M30 (3×/week), initiated 8 days after STZ-icv administration dosedependently ameliorated already developed cognitive deficits in MWM test (reduced number of mistakes 3 months after the STZ-icv treatment — 59%; p b 0.05) and fully restored them in PA test (+314%; p b 0.05). Chronic M30 treatment fully restored (−47%/PHF1;−65%/AT8; p b 0.05) STZ-induced hyperphosphorylation of tau protein and normalized decreased expression of insulin degrading enzyme (+37%; p b 0.05) in hippocampus.SIGNIFICANCEThe results provide first evidence of therapeutic potential of M30 and HLA20 in STZ-icv rat model of sAD with underlying molecular mechanism, further supporting the important role of multi-target ironchelators in sAD treatment.

01 Oct 2013·Current Pharmaceutical DesignQ4 · MEDICINE

Defective HIF Signaling Pathway and Brain Response to Hypoxia in Neurodegenerative Diseases: Not an “Iffy” Question!

Q4 · MEDICINE

Review

Author: Cristina Carvalho ; Paula I. Moreira ; Renato X. Santos ; Ana I. Duarte ; Ana I. Plácido ; Sónia C. Correia ; Susana Cardoso ; Emanuel Candeias

Brain structural and functional integrity exquisitely relies on a regular supply of oxygen. In order to circumvent the potential deleterious consequences of deficient oxygen availability, brain triggers endogenous adaptive and pro-survival mechanisms - a phenomenon known as brain hypoxic tolerance. The highly conserved hypoxia-inducible family (HIF) of transcription factors is the "headquarter" of the homeostatic response of the brain to hypoxia. HIF acts as a cellular oxygen sensor and regulates the expression of proteins involved in a broad range of biological processes, including neurogenesis, angiogenesis, erythropoiesis, and glucose metabolism, and thus, enables brain cells to survive in low-oxygen conditions. Hypoxia, as well as hypoxia-reoxygenation, is intimately implicated in the clinical and pathological course of several neurodegenerative diseases. Thus, two major questions can arise: Is HIF signaling and brain response to hypoxia compromised in neurodegenerative diseases? If so, are HIF stabilizers a possible therapeutic strategy to halt or prevent the progression of neurodegenerative diseases? This review highlights the current knowledge pertaining the role of HIF on brain response to hypoxia and its close association with the development of Alzheimer's, and Parkinson's disease and amyotrophic lateral sclerosis. Finally, the potential therapeutic effects of HIF stabilizers (deferoxamine, clioquinol, M30, HLA20, DHB, FG0041, and VK-28) against the symptomatic and neuropathological features of the abovementioned neurodegenerative diseases will be discussed.

30 Mar 2013·Experimental NeurobiologyQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: Youdim, Moussa B.H.

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Neurodegenerative Diseases	Discovery	IL	Varinel, Inc.	-

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