Novel multipotent AChEI-CCB attenuates hyperhomocysteinemia-induced memory deficits and Neuropathologies in rats.

Alzheimer's disease (AD) has multiple etiopathogenic factors, yet the definitive cause remains unclear and the therapeutic strategies have been elusive. Combination therapy, as one of the promising treatments, has been studied for years and may exert synergistic beneficial effects on AD through polytherapeutic targets. In this study, we tested the effects of a synthesized juxtaposition (named SCR1693) composed of an acetylcholinesterase inhibitor (AChEI) and a calcium channel blocker (CCB) on the hyperhomocysteinemia (HHcy)-induced AD rat model, and found that SCR1693 remarkably improved the HHcy-induced memory deficits and preserved dendrite morphologies as well as spine density by upregulating synapse-associated proteins PSD95 and synapsin-1. In addition, SCR1693 attenuated HHcy-induced tau hyperphosphorylation at multiple AD-associated sites by regulating the activity of protein phosphatase-2A and glycogen synthase kinase-3β. Furthermore, SCR1693 was more effective than individual administration of both donepezil and nilvadipine which were used as AChEI and CCB, respectively, in the clinical practice. In conclusion, our data suggest that the polytherapeutic targeting juxtaposition SCR1693 (AChEI-CCB) is a promising therapeutic candidate for AD.

[1]  S. Tyagi,et al.  Hydrogen sulfide attenuates neurodegeneration and neurovascular dysfunction induced by intracerebral-administered homocysteine in mice , 2013, Neuroscience.

[2]  I. Bezprozvanny,et al.  Can the Calcium Hypothesis Explain Synaptic Loss in Alzheimer's Disease? , 2013, Neurodegenerative Diseases.

[3]  A. Paetau,et al.  Plasma homocysteine, Alzheimer and cerebrovascular pathology: a population-based autopsy study. , 2013, Brain : a journal of neurology.

[4]  Jian-Zhi Wang,et al.  Cleavage of GSK‐3β by calpain counteracts the inhibitory effect of Ser9 phosphorylation on GSK‐3β activity induced by H2O2 , 2013, Journal of Neurochemistry.

[5]  Hashwin V. S. Ganesh,et al.  Biological activity of sym-triazines with acetylcholine-like substitutions as multitarget modulators of Alzheimer's disease. , 2013, ACS chemical neuroscience.

[6]  Xia Jiang,et al.  Betaine attenuates Alzheimer‐like pathological changes and memory deficits induced by homocysteine , 2013, Journal of neurochemistry.

[7]  Surojit Paul,et al.  Novel crosstalk between ERK MAPK and p38 MAPK leads to homocysteine‐NMDA receptor‐mediated neuronal cell death , 2013, Journal of neurochemistry.

[8]  I. Grundke‐Iqbal,et al.  Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. , 2012, Journal of Alzheimer's disease : JAD.

[9]  B. Dittrich,et al.  Electron density study of the anti-Alzheimer's disease drug donepezil from conventional x-ray data and invariom database application. , 2012, Future medicinal chemistry.

[10]  Xi-can Tang,et al.  Huperzine a alleviates synaptic deficits and modulates amyloidogenic and nonamyloidogenic pathways in APPswe/PS1dE9 transgenic mice , 2012, Journal of neuroscience research.

[11]  Cheng-Sheng Chen,et al.  PLASMA HOMOCYSTEINE LEVEL AND APATHY IN ALZHEIMER'S DISEASE , 2011, Journal of the American Geriatrics Society.

[12]  Xue Hua,et al.  Homocysteine effects on brain volumes mapped in 732 elderly individuals , 2011, Neuroreport.

[13]  C. Volmar,et al.  Selective Antihypertensive Dihydropyridines Lower Aβ Accumulation by Targeting both the Production and the Clearance of Aβ across the Blood-Brain Barrier , 2011, Molecular medicine.

[14]  R. Linden,et al.  The carboxy‐terminal fragment of inhibitor‐2 of protein phosphatase‐2A induces Alzheimer disease pathology and cognitive impairment , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  Richard Mooney,et al.  Rapid spine stabilization and synaptic enhancement at the onset of behavioural learning , 2010, Nature.

[16]  Jia-min Zhuo,et al.  Diet-induced hyperhomocysteinemia increases amyloid-beta formation and deposition in a mouse model of Alzheimer's disease. , 2009, Current Alzheimer research.

[17]  Ivan V. Goussakov,et al.  Deviant Ryanodine Receptor-Mediated Calcium Release Resets Synaptic Homeostasis in Presymptomatic 3xTg-AD Mice , 2009, The Journal of Neuroscience.

[18]  Q. Tian,et al.  Hyperhomocysteinemia increases beta-amyloid by enhancing expression of gamma-secretase and phosphorylation of amyloid precursor protein in rat brain. , 2009, The American journal of pathology.

[19]  T. Bonhoeffer,et al.  Experience leaves a lasting structural trace in cortical circuits , 2008, Nature.

[20]  Dao-Wen Wang,et al.  Homocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus , 2008, Neurobiology of Aging.

[21]  F. D’Anselmi,et al.  B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-β deposition in mice , 2008, Molecular and Cellular Neuroscience.

[22]  S. E. Black,et al.  Donepezil preserves cognition and global function in patients with severe Alzheimer disease , 2007, Neurology.

[23]  R. Diaz-Arrastia,et al.  Protein Phosphatase 2A Methyltransferase Links Homocysteine Metabolism with Tau and Amyloid Precursor Protein Regulation , 2007, The Journal of Neuroscience.

[24]  I. Grundke‐Iqbal,et al.  Alzheimer neurofibrillary degeneration: significance, etiopathogenesis, therapeutics and prevention , 2007, Journal of cellular and molecular medicine.

[25]  I. Grundke‐Iqbal,et al.  Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration , 2007, The European journal of neuroscience.

[26]  M. Pappolla,et al.  Hyperhomocysteinemic Alzheimer's mouse model of amyloidosis shows increased brain amyloid β peptide levels , 2006, Neurobiology of Disease.

[27]  H. Feldman,et al.  Efficacy and safety of donepezil in patients with more severe Alzheimer's disease: a subgroup analysis from a randomized, placebo‐controlled trial , 2005, International journal of geriatric psychiatry.

[28]  Fiona Crawford,et al.  Nilvadipine antagonizes both Aβ vasoactivity in isolated arteries, and the reduced cerebral blood flow in APPsw transgenic mice , 2004, Brain Research.

[29]  T. Shea,et al.  Multiple aspects of homocysteine neurotoxicity: Glutamate excitotoxicity, kinase hyperactivation and DNA damage , 2002, Journal of neuroscience research.

[30]  Jan A Staessen,et al.  The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. , 2002, Archives of internal medicine.

[31]  Sudha Seshadri,et al.  Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer's Disease , 2002 .

[32]  V. Talesa.  Acetylcholinesterase in Alzheimer's disease , 2001, Mechanisms of Ageing and Development.

[33]  H. Feldman,et al.  A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease , 2001, Neurology.

[34]  N. Inestrosa,et al.  Acetylcholinesterase–amyloid‐β‐peptide interaction and Wnt signaling involvement in Aβ neurotoxicity , 2000 .

[35]  R. Nicoll,et al.  PSD-95 involvement in maturation of excitatory synapses. , 2000, Science.

[36]  D. Campion,et al.  The pathogenic L392V mutation of presenilin 1 decreases the affinity to glycogen synthase kinase-3β , 2000, Neuroscience Letters.

[37]  G. Wilcock,et al.  The cholinergic hypothesis of Alzheimer’s disease: a review of progress , 1999, Journal of neurology, neurosurgery, and psychiatry.

[38]  I. Grundke‐Iqbal,et al.  τ is phosphorylated by GSK‐3 at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A‐kinase , 1998, FEBS letters.

[39]  K. Imahori,et al.  Characterization of tau phosphorylation in glycogen synthase kinase-3beta and cyclin dependent kinase-5 activator (p23) transfected cells. , 1998, Biochimica et biophysica acta.

[40]  M. Mattson,et al.  Calcium and reactive oxygen species mediate staurosporine‐induced mitochondrial dysfunction and apoptosis in PC12 cells , 1998, Journal of neuroscience research.

[41]  I. Grundke‐Iqbal,et al.  Restoration of biological activity of Alzheimer abnormally phosphorylated tau by dephosphorylation with protein phosphatase-2A, -2B and -1. , 1996, Brain research. Molecular brain research.

[42]  Claudia Linker,et al.  Acetylcholinesterase Accelerates Assembly of Amyloid-β-Peptides into Alzheimer's Fibrils: Possible Role of the Peripheral Site of the Enzyme , 1996, Neuron.

[43]  Khadija Iqbal,et al.  Modulation of GSK‐3‐catalyzed phosphorylation of microtubule‐associated protein tau by non‐proline‐dependent protein kinases , 1995, FEBS letters.

[44]  M. Mattson,et al.  β-Amyloid precursor protein and alzheimer's disease: The peptide plot thickens , 1992, Neurobiology of Aging.

[45]  H. Braak,et al.  Occurrence of neuropil threads in the senile human brain and in Alzheimer's disease: A third location of paired helical filaments outside of neurofibrillary tangles and neuritic plaques , 1986, Neuroscience Letters.

[46]  R. Morris.  Developments of a water-maze procedure for studying spatial learning in the rat , 1984, Journal of Neuroscience Methods.

[47]  T. Ueda,et al.  Distribution of Protein I, a Synapse‐Specific Phosphoprotein, and Adenylate Cyclase in the Rat Spinal Cord , 1981, Journal of neurochemistry.

[48]  D. Selkoe,et al.  Biochemistry of altered brain proteins in Alzheimer's disease. , 1989, Annual review of neuroscience.