I2-Imidazoline Ligand CR4056 Improves Memory, Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice.

Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer's disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reductions in amyloid-ß (Aß) deposition. In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. Sub-chronic oral administration of CR4056 (30 mg/kg for 10 days) led to an improvement in recognition memory in 6-month-old 5xFAD mice, but not in wild-type littermates, without affecting Aß levels or deposition. Our results also revealed a change in the profile of microglia by CR4056, resulting in a suppression of pro-inflammatory activated microglia, but increased the density of astrocytes and the expression of ApoE, which is mainly produced by these glial cells. In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aß-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD.

Education provision in community setting increases engagement with bowel cancer screening.

In the United Kingdom, colorectal carcinoma (CRC) is the third most prevalent and second most lethal cancer, accounting for 1 in 10 cancer deaths. To address this health burden, the NHS implemented a national screening programme to detect traces of blood in the stool of those at highest risk of CRC - men and women aged over 60. Preliminary data showed that the screening programme reduced CRC death by 16% overall and 23% in those who had returned their kit, highlighting the importance of patient engagement. Worryingly, recent data has indicated that engagement with the screening programme has begun to decline. Many GP surgeries are failing to achieve the 75% quota set by the Quality and Outcomes Framework, with London performing least favourably within the UK. To address this, we set up an educational intervention at a London GP practice, targeting misconceptions and anxieties associated with bowel screening and CRC in general, to assess whether this would improve patients' confidence in returning a stool sample as suggested by previous studies. Our results came to promising conclusions, but we remain cautious that our preliminary findings are subject to confounding influences which prevent conclusion of a causal relationship.