title: Ibuprofen and lipoic acid conjugate neuroprotective activity is mediated by Ngb/Akt intracellular signaling pathway in Alzheimer's disease rat model.
abstract: BACKGROUND
  Alzheimer's disease (AD) is a frequent form of senile dementia. Neuroglobin (Ngb) has a neuroprotective role and decreases Aβ peptide levels. Ngb, promoting Akt phosphorylation, activates cell survival involving cyclic-nucleotide response element-binding protein (CREB). A new molecule (IBU-LA) was synthetized and administered to an AD rat model to counteract AD progression.
  
  
  OBJECTIVE
  The aim of this study was to investigate the IBU-LA-mediated induction of Ngb neuroprotective and antiapoptotic activities.
  
  
  METHODS
  Brain morphology was analyzed through Bielschowsky staining, Aβ(1-40) and Ngb expression by immunohistochemistry. Akt, p-Akt, CREB and p-CREB expression was evaluated by Western blot, apoptosis through cytochrome C/Apaf 1 immunocomplex formation, and TUNEL analysis.
  
  
  RESULTS
  Bielschowsky staining and Aβ(1-40) expression show few nerve connections and Aβ(1-40) expression in an Aβ sample, preserved neuronal cells and Aβ(1-40) expression lowering in an IBU sample, mostly in IBU-LA. The Ngb level decreases in Aβ samples, compared to control and IBU-LA samples. p-Akt/Akt and p-CREB/CREB ratios reveal a reduction in Aβ sample, going back to the basal level in control and IBU-LA samples. Cytochrome C/Apaf 1 co-immunoprecipitate occurs and TUNEL-positive nuclei percentage decreases in Aβ sample. Probe test performance shows an increased spatial reference memory in the IBU-LA compared to the Aβ sample; no significant differences were seen between the IBU-LA and IBU samples.
  
  
  CONCLUSIONS
  This evidence reveals that IBU-LA administration has the capability to maintain a high Ngb level allowing Ngb to perform a neuroprotective and antiapoptotic role, representing a valid tool in the therapeutic strategy of AD progression.
authors: Dipartimento di Farmacia, Università 'G. d'Annunzio', Chieti, Italia. s.zara@unich.it
authors: Susi
authors: S
authors: Zara
authors: Marianna
authors: M
authors: De Colli
authors: Monica
authors: M
authors: Rapino
authors: Stephanie
authors: S
authors: Pacella
authors: Cinzia
authors: C
authors: Nasuti
authors: Piera
authors: P
authors: Sozio
authors: Antonio
authors: A
authors: Di Stefano
authors: Amelia
authors: A
authors: Cataldi
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005914:Globins / Q000378:metabolism*; D006801:Humans; D007052:Ibuprofen / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000078787:Neuroglobin; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D008063:Thioctic Acid / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D000078787:Neuroglobin; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D008063:Thioctic Acid; D005914:Globins; D051057:Proto-Oncogene Proteins c-akt; D007052:Ibuprofen