ABSTRACT
Neural Cell Adhesion Molecules [NCAMs] are known to influence memory by affecting neural cell-cell and cell-extracellular matrix junctions. This study investigated the possible role of cAMP pathway in the expression of hippocampal NCAM and its polysialylated derivative [PSA-NCAM]. The following pharmacological tools were employed for manipulation of cAMP pathway: a] forskolin; the activator of adenylyl cyclase [AC], b] 8-Br-cAMP; a protein kinase A [PKA] agonist, c] 8-pCPT-2'-O-Me-cAMP; a selective enhancer of exchange protein activated by cAMP [Epac] and d] Rp-cAMP; a PKA inhibitor. Memory acquisition was tested by passive avoidance paradigm after injecting the above compounds for three consecutive days into the CA1 region of dorsal hippocampus of rats. Forskolin and 8-Br-cAMP enhanced memory retrieval while Rp-cAMP significantly reduced memory and NCAM levels. 8-pCPT-2'-O-Me-cAMP failed to alter memory performance or NCAM levels as compared to vehicle. We observed no significant changes in PSA-NCAM, however the expression of St8sia4 and St8sia2 [the polysialyltransferase isoforms] were altered. The mRNA levels of St8sia4 was down-regulated by 8-Br-cAMP, Rp-cAMP and 8-pCPT while forskolin led to almost 3 and 5 fold increase in mRNAs of St8sia2 and St8sia4, respectively. The current insight might endorse the predominant role of PKA as compared to Epac in cAMP pathway in expression of NCAM and memory function
ABSTRACT
Chalcone [1, 3-diarylprop-2-en-1-one] derivatives have been introduced as selective cyclooxygenase-2 inhibitors. In the present study, anti-nociceptive and anti-inflammatory effects of eight novel compounds were evaluated in male mice and Wistar rats by using the writhing and formalin-induced paw edema tests respectively. The activities of the compounds were compared with celecoxib as a reference drug. Then, novel compounds were divided into two regioisomeric groups based on the position of the methyl sulfonyl substitution. Compounds with substituents such as: 1] H, 2] Me, 3] F and 4] Cl at para position of the phenyl ring of [E]-3-[4-Methanesulfonylphenyl]-1-phenylprop-2-en-1-one were selected in the first group. The regioisomer compounds with 5] H, 6] Me, 7] F and 8] OMe substitutions at C-4 of phenyl ring of [E]-1-[4-Methanesulfonylphenyl]-3-phenylprop-2-en-1-one were chosen as second group. All compounds showed dose-dependent anti-nociceptive activity in writhing test. Interestingly, the potency of anti-nociceptive effect of compounds 1, 2, 5 and 6 were significantly higher than celecoxib. The regioisomeric compounds 1 and 5 with high anti-nociceptive effects, showed a significant dose-dependent anti-inflammatory activity in the paw edema test as well. The results showed that compounds with no substituent or small size substituents at para position of the phenyl ring are the most potent compound in writhing test. Our results revealed that the introduction of a bulky group such as methoxy or chlorine at the vicinal aromatic chain of the derivatives decreases the anti-inflammatory/anti-nociceptive effects. The comparison of estimated ED[50] of each pair of the regioisomeric compounds indicates that the relative position of SO[2]Me to carbonyl moiety did not affect the potency