The peptide nociceptin (also named orphanin FQ) acts in the brain to produce various pharmacological effects, including hyperalgesia and hypolocomotion. The nociceptin receptor uses guanine-nucleotide-binding proteins to mediate the inhibition of adenylyl cyclase, the activation of potassium channels and inhibition of calcium channels. It has been shown using knock-out mice that the nociceptin receptor is not required for regulation of nociceptive responses or locomotion activity, but modulates the auditory function. Here we show that mice lacking the nociceptin receptor possess greater learning ability and have better memory than control mice. Histological analysis revealed the expression of both the nociceptin precursor and the nociceptin receptor in the hippocampus, thought to take part in aspects of learning and memory. Moreover, the receptor-deficient mice showed larger long-term potentiation in the hippocampal CA1 region than control mice, without apparent changes in presynaptic or postsynaptic electrophysiological properties. These results show that the loss of the nociceptin receptor results in a gain-of-function mutation in both the memory process and the long-term potentiation mechanism in CA1, perhaps as a result of altered intracellular signal transduction systems in neurons.

Tumor necrosis factor-␣ (TNF-␣

Background: Midkine (MK) is a growth factor implicated in the development and repair of various tissues, especially neural tissues. However, its in vivo function has not been clarified.

Background and purpose: Accumulated evidence suggests that oxidative stress is involved in amyloid b (Ab)-induced cognitive dysfunction. Silibinin (silybin), a flavonoid derived from the herb milk thistle (Silybum marianum), has been shown to have antioxidative properties; however, it remains unclear whether silibinin improves Ab-induced neurotoxicity. In the present study, we examined the effect of silibinin on the memory impairment and accumulation of oxidative stress induced by Ab25-35 in mice. , once a day, p.o.) was started immediately after the injection of Ab25-35. Locomotor activity was evaluated 6 days after the Ab25-35 treatment, and cognitive function was evaluated in a Y-maze and novel object recognition tests 6-11 days after the Ab25-35 treatment. The levels of lipid peroxidation (malondialdehyde) and antioxidant (glutathione) in the hippocampus were measured 7 days after the Ab25-35 injection. Key results: Silibinin prevented the memory impairment induced by Ab25-35 in the Y-maze and novel object recognition tests. Repeated treatment with silibinin attenuated the Ab25-35-induced accumulation of malondialdehyde and depletion of glutathione in the hippocampus. Conclusions and implications:Silibinin prevents memory impairment and oxidative damage induced by Ab25-35 and may be a potential therapeutic agent for Alzheimer's disease.

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