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In the water-maze test, the linoleic acid derivative, 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) (1 mg/kg, intraperitoneally), significantly shortened the prolonged latency for accelerated-senescence-prone mice 8 (SAMP8), reaching a level similar to the latency for accelerated-senescence-resistant mice 1 (SAMR1) as control. In the open-field test to assess motor activity, it was confirmed that the DCP-LA effect is not due to increased motor activity. In the passive avoidance test to assess fear memory, DCP-LA had no effect on the latency of acquisition and retention for SAMP8. The results of the present study, thus, suggest that DCP-LA could improve age-related learning impairment by enhancing cognitive functions.

Abstract: Long-term potentiation (LTP) was monitored from the CA1 region of the intact rat hippocampus by delivering high frequency stimulation (HFS) to the Schaffer collateral commissural pathway. Intraventricular injection with mutant amyloid β1–42 peptide lacking glutamate-22 (Aβ1–42E22Δ), favoring oligomerization, 10min prior to HFS, inhibited expression of LTP, with the potency more than wild-type amyloid β1–42 peptide. Intraperitoneal injection with the linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) 70min prior to HFS neutralized mutant Aβ1–42E22Δ peptide-induced LTP inhibition. In the water maze test, continuous intraventricular injection with mutant Aβ1–42E22Δ peptide for 14 days prolonged the acquisition latency as compared with that for control, with the potency similar to wild-type Aβ1–42 peptide, and intraperitoneal injection with DCP-LA shortened the prolonged latency to control levels. The results of the present study indicate that DCP-LA neutralizes mutant Aβ1–42E22Δ peptide-induced impairment of LTP and spatial learning. [Copyright &y& Elsevier]

The linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) activated Ca2+/calmodulin-dependent protein kinase II (CaMKII) by inhibiting protein phosphatase-1 (PP-1). DCP-LA induced a transient huge facilitation of synaptic transmission monitored from the CA1 region of rat hippocampal slices, which was largely inhibited by the CaMKII inhibitor KN-93. DCP-LA potentiated kainate-evoked whole-cell membrane currents for Xenopus oocytes expressing α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors composed of the GluR1, GluR3, GluR1/GluR2, GluR1/GluR3, and GluR1/GluR2/GluR3 subunits, and the potentiation was significantly inhibited by KN-93. A similar potentiation was still found with mutant GluR1 (S831A) receptor lacking CaMKII phosphorylation site. The GluR1 and GluR2 subunits formed AMPA receptors in the rat hippocampus, and DCP-LA increased expression of both the subunits on the plasma membrane. The DCP-LA action was blocked by KN-93 and the exocytosis inhibitor botulinum toxin type A, but not by the endocytosis inhibitor phenylarsine oxide. DCP-LA, thus, appears to activate CaMKII through PP-1 inhibition, that stimulates AMPA receptor exocytosis to increase expression of the receptors on the plasma membrane, responsible for potentiate AMPA receptor responses and facilitation of hippocampal synaptic transmission. J. Cell. Physiol. 221: 183–188, 2009. © 2009 Wiley-Liss, Inc [ABSTRACT FROM AUTHOR]

Background: In our earlier study, 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA), a newly synthesized linoleic acid derivative with cyclopropane rings instead of cis-double bonds, facilitated hippocampal synaptic transmission by stimulating glutamate release from presynaptic terminals as mediated via α7 acetylcholine (Ach) receptors under the influence of protein kinase C. The present study assessed the possibility of using DCP-LA as a cognitive enhancer in animal models. Methods: Amyloid-β1−40 peptide (300 pM/day) or saline was continuously injected in the right lateral ventricle of rats for 2 weeks. Then, the water maze test was carried out, once per day for 7 days, 1 h after the intraperitoneal injection with DCP-LA or saline. In a different set of experiments, rats were intraperitoneally injected with scopolamine (1 mg/kg) and the water maze test was performed twice per day, with the first test taking place 1 h after the intraperitoneal injection with DCP-LA, galantamine or saline, and the second test starting 2 min after the end of the first. Results: Continuous intraventricular injection with amyloid-β1−40 peptide in the rat lateral ventricle prolonged the latency for acquisition in the water maze test. DCP-LA (1 mg/kg, intraperitoneal (i.p.)) significantly improved the impairment, which reached a level similar to the latency for sham. Furthermore, DCP-LA (1 mg/kg, i.p.) significantly ameliorated learning and memory deficits in rats treated with scopolamine and was, if not more, effective than galantamine, a modest inhibitor of acetylcholinesterase with nicotinic ACh receptor modulation. Conclusion: The results of the present study show that DCP-LA ameliorates learning and memory deficits induced by amyloid-β1−40 peptide or scopolamine. DCP-LA may thus offer new hope for dementia patients. [ABSTRACT FROM AUTHOR]

Abstract: Linoleic acid (C18:2ω6) (10 μM) depressed ACh-evoked whole-cell membrane currents followed by potentiation of the currents in Xenopus oocytes expressing Torpedo ACh receptors. The potentiation was never obtained with linoleoylamide (10 μM), which contains CONH2 instead of COOH on linoleic acid. In the assay of protein kinase C (PKC) using a reversed phase high-performance liquid chromatography, linoleic acid activated PKC-ε but linoleoylamide otherwise had no effect on it. Of a variety of cis-unsaturated free fatty acids with 20 hydrocarbon chains (C20), 8-eicosenoic acid (C20:1ω12) potentiated ACh receptor channel currents without depression. 11,14-Eicosadienoic acid (C20:2ω6), 5,8,11-eicosatrienoic acid (C20:3ω9), 5,8,11,14-eicosatetraenoic acid (arachidonic acid) (C20:4ω6), and 5,8,11,14,17-eicosapentaenoic acid (C20:5ω3) depressed and potentiated the currents. In contrast, only a depression was obtained with 5-eicosenoic acid (C20:1ω15), 11-eicosenoic acid (C20:1ω9), and 8,11,14-eicosatrienoic acid (C20:3ω6). All the free fatty acids (C20) involved PKC-ε activation, with no significant difference in the potency among them. Taken together, it appears that carboxyl on cis-unsaturated free fatty acids plays a significant role in PKC-ε activation and potentiation of nicotinic ACh receptor responses. The role of the number and position of the cis-double bonds in the receptor responses, however, remains an open question. [Copyright &y& Elsevier]