NOS-mediated morphological and molecular modifications in rats infused with A beta (1-40), as a model of Alzheimer's disease, in response to a new lipophilic molecular combination codrug-1

作者：Zara Susi; Di Stefano Antonio; Nasuti Cinzia; Rapino Monica; Patruno Antonia; Pesce Mirko; Sozio Piera; Cerasa Laura S; Cataldi Amelia^*

来源：Experimental Gerontology, 2011, 46(4): 273-281.

DOI：10.1016/j.exger.2010.11.001

• Alzheimer's disease
• Rat brain
• Ibuprofen
• Codrug 1
• Nitric oxide synthases

Alzheimer's disease is a neurodegenerative pathology due to the presence of beta-amyloid plaques at brain level and hippocampus level and associated with the loss of memory speech and learning. At the basis of these effects lie molecular mechanisms which include nitric oxide metabolic pathway, whose involvement in the occurrence of morphological modifications related to such neurodegenerative process is suggested. Current evidences show that the non-steroidal anti-inflammatory drug ibuprofen posses a protective effect against the development of the disease, substantially delaying its onset; furthermore (R)-alpha-lipoic acid seems to have an antioxidant ameliorating effect on disease progression. Starting from these data, a new lipophilic codrug 1, obtained by joining an antioxidant molecule with an NSAID, has been previously synthesized. Our aim has been to investigate the possible therapeutical effects of codrug 1, compared to ibuprofen, on the molecular events at the basis of behavioural and morphological modifications occurring in A beta (1-40) infused rat brains. Ibuprofen and codrug 1 seem to protect the subject against memory performance impairment and against behavioural detriment, induced by administration of A beta (1-40) peptide. Such evidences are supported by morphological and biochemical findings showing A beta (1-40) to determine cell disorganization, increased number of beta-amyloid plaques and capillary vessels dilatation in parallel to increased total and specific NOS activity and to apoptosis occurrence, partly prevented by ibuprofen, more broadly by codrug 1. Such results underline the involvement of nitric oxide metabolic pathway in the events related to the onset of this pathology and suggest codrug 1 as a useful tool to protect the brain against cognitive and behavioural dysfunction, by reducing beta-amyloid plaques formation and by inhibiting NOS signalling pathway and apoptosis occurrence.

• 出版日期2011-4