Imbalanced lipid metabolism and increase in the ceramide-to-S1P ratio in the brain have been postulated to play a role in amyloidogenesis, neuroinflammatory reactions, and neuronal apoptosis in Alzheimer's disease (AD) pathology. FTY720, the immunomodulatory sphingosine 1-phosphate (S1P) analog, has recently gained interest because of its CNS-directed effects. In addition to its immunomodulatory functions in multiple sclerosis, FTY720 possesses anti-inflammatory and neuroprotective roles in different cerebral ischemia models. In the present study, we examined the effects of FTY720 in a rat model of AD. Memory deficit was induced by bilateral intrahippocampus injection of beta-amyloid peptide (Aβ(42)) and examined through the Morris water maze test. The extent of histological injury in the hippocampus and the activation of caspase-3 were determined respectively by Nissl staining and Western blotting. Chronic daily administration of FTY720 (1 mg/kg, i.p., 14 days) significantly attenuated the Aβ(42)-induced learning and memory impairment and prevented the hippocampus neuronal damage as well as caspase-3 activation. These data show for the first time that FTY720 has a beneficial effect in restoring memory loss in Aβ(42)-induced neurotoxicity and also suggest that S1P receptors and signaling pathways may provide a potential target for the treatment of AD.

Nicotinamide phosphoribosyl transferase/pre-B cell colony-enhancing factor/visfatin (Nampt/PBEF/visfatin) is an adipocytokine. By synthesizing nicotinamide adenine dinucleotide (NAD(+)), Nampt/PBEF/visfatin functions to maintain an energy supply that has critical roles in cell survival. Cerebral ischemia leads to energy depletion and eventually neuronal death by apoptosis in specific brain regions specially the hippocampus. However, the role of Nampt/PBEF/visfatin in brain and cerebral ischemia remains to be investigated. This study investigated the role of administration Nampt/PBEF/visfatin in hippocampal CA3 area using a transient global cerebral ischemia model. Both common carotid arteries were occluded for 20 min followed by reperfusion. Saline as a vehicle and Nampt/PBEF/visfatin at a dose of 100 ng were injected intracerebroventricularly (ICV) at the time of cerebral reperfusion. To investigate the underlying mechanisms of Nampt/PBEF/visfatin neuroprotection, levels of expression of apoptosis-related proteins (caspase-3 activation, Bax protein levels, and Bcl-2 protein levels) 96 h after ischemia were determined by immunohistochemical staining. The number of active caspase-3-positive neurons in CA3 was significantly increased in the ischemia group, compared with the sham group (P < 0.001), and treatment with Nampt/PBEF/visfatin significantly reduced the ischemia/reperfusion-induced caspase-3 activation, compared to the ischemia group (P < 0.05). Also, results indicated a significant increase in Bax/Bcl-2 ratio in the ischemia group, compared with the sham group (P < 0.01). However, treatment with Nampt/PBEF/visfatin significantly attenuated the ischemia/reperfusion-induced increase in Bax/Bcl-2 ratio, compared with the ischemia group (P < 0.05). This study has indicated that Nampt/PBEF/visfatin entails neuroprotective effects against ischemia injury when used at the time of cerebral reperfusion. These neuroprotective mechanisms of Nampt/PBEF/visfatin occur through decrease the expression ofproapoptotic proteins (cleaved caspase-3 and Bax) and, on the other hand, increase the expression ofantiapoptotic proteins (Bcl-2). Thus, our findings indicate that Nampt/PBEF/visfatin is a new therapeutic target for cerebral ischemia.

There is evidence that both cholinergic and GABAergic systems are involved in the neurobiology of anxiety. In the present study, we investigated the effects and interaction of nicotinic and GABAergic systems in the central amygdala of rats, using the elevated plus maze test of anxiety. Bilateral administration of nicotine (1 and 2 µg/rat; 1 µl/rat; 0.5 µl/rat in each side) into the central amygdala (intra-CeA) induced an anxiogenic-like effect, shown by specific decreases in the percentage of open-arm time (%OAT) and percentage of open arm entries (%OAE). Intra-CeA injection of mecamylamine, a selective nicotine acetylcholine receptor antagonist (20, 30 and 50 ng/rat; 1 µl/rat; 0.5 µl/rat in each side) produced significant anxiolytic-like behaviour. The intra-CeA injection of the GABA_A receptor agonist muscimol (0.25, 0.5 and 0.75 µg/rat; 1 µl/rat; 0.5 µl/rat in each side) decreased %OAT and %OAE, indicating anxiogenic-like behaviour. However, intra-CeA administration of the GABA_A receptor antagonist bicuculline (0.25, 0.5 and 1 µg/rat; 1 µl/rat; 0.5 µl/rat in each side) produced significant anxiolytic-like behaviour. Nicotine in a subeffective dose (0.25 µg/rat) when co-administered with muscimol did not significantly increase the anxiety behaviour. An effective dose of nicotine (2 µg/rat) in combination with bicuculline (0.25, 0.5 and 1 µg/rat) had no interaction on %OAT, %OAE and locomotor activity. It can be concluded that in the central amygdala, the GABAergic system is not involved in the anxiogenic response to nicotine.

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In the present study, the effects of the histamine and cholinergic systems on memory retention in adult male rats were investigated. Post-training intracerebroventricular injections were carried out in all the experiments. Cholinoceptor agonist, acetylcholine (1-10 microg/rat) or nicotine (1-10 microg/rat), increased, while a cholinoceptor antagonist, scopolamine (5-20 microg/rat), decreased memory retention. The response to acetylcholine was attenuated by scopolamine. Administration of histamine (5-20 microg/rat) reduced, but the histamine H(1) receptor antagonist, pyrilamine (10-50 microg/rat), and the histamine H(2) receptor antagonist, cimetidine (1-50 microg/rat), increased memory retention in rats. The histamine receptor antagonists attenuated the response to histamine. Histamine reduced the acetylcholine- or nicotine-induced enhancement. The histamine receptor antagonists enhanced the nicotine- or acetylcholine-induced response. Histamine potentiated the inhibitory effect induced by scopolamine. It is concluded that histaminergic and cholinergic systems have opposing effects on memory retention. Also, the histaminergic system elicits an interaction with the cholinergic system in memory retention.

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