NOS-mediated morphological and molecular modifications in rats infused with Aβ (1-40), as a model of Alzheimer's disease, in response to a new lipophilic molecular combination codrug-1.
Alzheimer's disease is a neurodegenerative pathology due to the presence of β-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)-α-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 Aβ (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 Aβ (1-40) peptide. Such evidences are supported by morphological and biochemical findings showing Aβ (1-40) to determine cell disorganization, increased number of β-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 β-amyloid plaques formation and by inhibiting NOS signalling pathway and apoptosis occurrence.
Dipartimento di Scienze del Farmaco, Università G. d'Annunzio, Chieti, Pescara, Italy.
Susi
S
Zara
Antonio
A
Di Stefano
Cinzia
C
Nasuti
Monica
M
Rapino
Antonia
A
Patruno
Mirko
M
Pesce
Piera
P
Sozio
Laura S
LS
Cerasa
Amelia
A
Cataldi
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000627:therapeutic use*; D000975:Antioxidants / Q000737:chemistry / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004338:Drug Combinations; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D004338:Drug Combinations; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496322:Nos1 protein, rat; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D007052:Ibuprofen