Effect of long term administration of tamoxifen on memory in male rat

Background and Objective: Tamoxifen is one of the selective estrogen receptor modulators that exerts estrogen / anti-estrogen effects in various tissues. This study was done to evaluate the effect of chronic administration of tamoxifen on spatial memory and passive avoidance task in adult male Wistar rats. Methods: In this experimental study, 48 adult male Wistar rats were randomly divided into control, sham and tamoxifen groups. Animals in sham and tamoxifen groups were received tamoxifen solution and tamoxifen (400mg/kg/day) orally for 35 consecutive days. At the end of treatment, spatial learning and memory of animals was assessed using the Morris water maze task and passive avoidance memory was examined using the shuttle box. Results: The time spent and distance moved to reach the platform, significantly increased in tamoxifen group compared to controls (P<0.05). In addition, the time spent and distance moved in the target quadrant (in the probe test) significantly reduced in tamoxifen group in compared to controls (P<0.05). In passive avoidance task, tamoxifen significantly decreased the time of the entrance to the dark room compared to control animals (P<0.05). Conclusion: Long-term administration of tamoxifen impairs spatial learning and memory and passive avoidance memory in rats

Loss of the neuroprotective factor Sphingosine 1-phosphate early in Alzheimer’s disease pathogenesis

BACKGROUND: The greatest genetic risk factor for late-onset Alzheimer's disease (AD) is the ϵ4 allele of Apolipoprotein E (ApoE). ApoE regulates secretion of the potent neuroprotective signaling lipid Sphingosine 1-phosphate (S1P). S1P is derived by phosphorylation of sphingosine, catalysed by sphingosine kinases 1 and 2 (SphK1 and 2), and SphK1 positively regulates glutamate secretion and synaptic strength in hippocampal neurons. S1P and its receptor family have been subject to intense pharmacological interest in recent years, following approval of the immunomodulatory drug Fingolimod, an S1P mimetic, for relapsing multiple sclerosis. RESULTS: We quantified S1P levels in six brain regions that are differentially affected by AD pathology, in a cohort of 34 post-mortem brains, divided into four groups based on Braak neurofibrillary tangle staging. S1P declined with increasing Braak stage, and this was most pronounced in brain regions most heavily affected by AD pathology. The S1P/sphingosine ratio was 66% and 64% lower in Braak stage III/IV hippocampus (p = 0.010) and inferior temporal cortex (p = 0.014), respectively, compared to controls. In accordance with this change, both SphK1 and SphK2 activity declined with increasing Braak pathology in the hippocampus (p = 0.032 and 0.047, respectively). S1P/sphingosine ratio was 2.5-fold higher in hippocampus of ApoE2 carriers compared to ApoE4 carriers, and multivariate regression showed a significant association between APOE genotype and hippocampal S1P/sphingosine (p = 0.0495), suggesting a new link between APOE genotype and pre-disposition to AD. CONCLUSIONS: This study demonstrates loss of S1P and sphingosine kinase activity early in AD pathogenesis, and prior to AD diagnosis. Our findings establish a rationale for further exploring S1P receptor pharmacology in the context of AD therapy