Abstract
Behavioural and psychological symptoms of dementia (BPSD), including fear-anxiety- and depressive-like behaviour, are present in Alzheimer’s disease (AD), together with memory decline. I2-imidazoline receptors (I2-IRs) have been associated with neuropsychiatric and neurodegenerative disorders, further, I2-IR ligands have demonstrated a neuroprotective role in the central nervous system (CNS). In this study, we assessed the effect of the I2-IR ligand MCR5 on both cognitive and non-cognitive symptoms in the Senescence accelerated mice prone 8 (SAMP8) mouse model. Oral administration of I2-IR ligand MCR5 (5 mg/kg/day for four weeks) in 10-month SAMP8 mice ameliorated both BPSD-like phenotype and cognitive decline by attenuating depressive-like behaviour, reducing fear-anxiety-like behaviour and improving cognitive performance using different tasks. Interaction of I2-IR ligand MCR5 with serotoninergic system did not account for behavioural or cognitive improvement, although changes in molecular pathways underlying depression and anxiety phenotype were observed. MCR5 increased levels of p-AKT, phosphorylated glycogen synthase kinase 3 β (GSK3β) at Ser9 and phosphorylated mammalian target of rapamycin complex 1 (mTORC1) levels in SAMP8 treated mice compared to SAMP8 control. Moreover, MCR5 treatment altered N-methyl-d-aspartate receptor (NMDA) 2B phosphorylation, and decreased the protein levels of phosphorylated cyclin-dependent kinase 5 (p-CDK5) and dopamine- and cyclic adenosine monophosphate (cAMP)-regulated phosphoprotein of Mr 32 kDa phosphorylated at Thr75 (p-DARPP32), with a parallel increase in protein kinase A (PKA) and p-cAMP response element-binding (pCREB) levels. Consistent with these changes MCR5 attenuated neuroinflammation by decreasing expression of pro-inflammatory markers such as Tumor necrosis factor-alpha (Tnf-α), Interleukin 1β (Il-1β), Interleukin 6 (Il-6), and promoted synaptic plasticity by increasing levels of postsynaptic density protein 95 (PSD95) as well as ameliorating tropomyosin-related kinase B (TrkB) and nerve growth factor receptor (NGFR) signalling. Collectively, these results increase the potential of highly selective I2-IR ligands as therapeutic agents in age-related BPSD and cognitive alterations.
Highlights
Nowadays, the global population of the elderly is increasing in parallel to the diagnosis of neurodegenerative diseases (ND) and psychiatric disorders
After treatment with MCR5, a significant increase in the discrimination index (DI) was obtained both in the Novel Object Recognition Test (NORT) short-term memory test (Figure 2B) and the NORT long-term memory test in treated Senescence accelerated mice prone 8 (SAMP8) compared to the SAMP8 control group (Figure 2C)
In Object Location Test (OLT), I2-imidazoline receptors (I2-IRs) treatment significantly improved spatial memory in treated SAMP8 compared to the SAMP8 control group by increasing the DI, further demonstrating the beneficial effect of MCR5 on cognitive loss associated to age in SAMP8 mice (Figure 2D)
Summary
The global population of the elderly is increasing in parallel to the diagnosis of neurodegenerative diseases (ND) and psychiatric disorders. Non-cognitive symptoms are becoming increasingly important due to their prevalence, generating several dysfunctions and representing one of the most troublesome domains of treating dementia [3] These non-cognitive symptoms that patients suffer, commonly referred to as “Behavioural and psychological symptoms of dementia” (BPSD), mainly include aberrant motor behaviour, hallucinations, aggressive and anxiety behaviour and depression, among others [4]. Agmatine, the endogenous I2-IR ligand [22], has a modulatory effect on anxiety and depression [23,24] Those studies that had utilized allegedly α2-selective imidazoline radioligands, i.e., [3H]-clonidine, could be reinterpreted in terms of the increased number of those receptors in depression. Besides the age-related cognitive decline that mainly characterizes the SAMP8 model, this strain displays anxiety- and depressive-like behaviour in comparison to their senescence-acceleration resistant counterparts, SAMR1 mice [28]. PharmaIcneuttichse202p0r, e12s,exnt study, we assessed the cognitive and non-cognitive effects, espe3coiaf l2ly0 anxiety- and antidepressant-like effects as the main BPSD behaviours of the I2-IR ligand cMhlCoRro5-4d-fileutohryolbe[(n1z-y(3l)--c5h,5lo-droim-4e-flthuyolr-o4-bpehneznyyl)l-54,5-dimhyedthroy-l1-4H--pimheindyalz-o4l,-54--dyilh)pyhdorosp-1hHo-nimateid] aiznolv-4iv-yol,) prhoovsipdhinognaatse]wienllvtihvaot, tphreoveivdidinegncaes rwefeelrlrtehdatothinedeuvcieddenmceolreecfuelrarredchtaonignedsutcheadt cmoouledcuexlaprlacihnasnugcehs ethffaetctcso,uuldsinegxptlhaeinSAsuMchP8effmecictse, musoindgel.thAesSaAfoMrePm8 emnitcioenmedo,dMel.CARs5 atfeosrteedmeinntpiorenveido,uMs CwRo5rktsesotfedouinr gprroeuvipo,upsrewseonrktesdonfeouurropgrrootuepct,ipvereasnedntaendanlgeeusricopefrfoetcetcst,isvheoawneddapnraolmgeissiicngeffreescutsl,tssihnomwoeddeplsroomf bisrianing dreasmulatgsein[2m6o] daenlds opfrbervaeinntdedamcaoggeni[t2iv6]eadnedclpinreeveinntSeAd McoPg8niatigveeddefecmlinaeleinmSiAceM, iPn8claugdeidngfemmaolleecmuilcaer, cinhcalnugdeisnagsmsoocilaetceudlawr icthhaanggeeasnadssnoecuiaroteddegweintehraatgieveapnrdonceesusreosd[2e7g]e.nTehruatsi,vweepsrtoucdeisesdesso[2m7e].mTohluesc,uwlaer pstauthdwiedayssormeleatmedolteocunleaurrpoadtehgwenayersarteiolanteadndtonneeuurroopdseygcehniaetrraictiodnisoanrddenrseuthraotpasryechchiaatrraicctdeirsiostridceorfsatghea-t raerleatcehdarbaechtearviisotiucroafl aagned-rceolgatneidtivbeehaabvnioorumraalliatineds ocof gSnAiMtivPe8a. bnormalities of SAMP8
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