Amelioration of BPSD-Like Phenotype and Cognitive Decline in SAMP8 Mice Model Accompanied by Molecular Changes after Treatment with I2-Imidazoline Receptor Ligand MCR5

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.

Disease‐modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: a comparative study with donepezil

“…On the other hand, inflammatory gene expression increase (Il-18 and Ccl12) was observed after treatment with I 2 ligand LSL60101 and LSL60101/donepezil, but not with donepezil. Interestingly, this was further supported by a significant up-regulation of Trem2 gene expression determined in the LSL60101-treated mice, further confirming the neuroinflammatory modulation by I 2 ligand LSL60101 (Griñ an-Ferré et al, 2019;Hwang et al, 2010;Vasilopoulou, Bagan, et al, 2020). In fact, increased Trem2 expression has been shown to reprogram microglia responsivity mediating microglial cytokine release, migration and clearance of amyloid-β deposits, ameliorating neuropathological and behavioural deficits of AD mouse models (Lee et al, 2018;Zhao et al, 2018).…”

Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer’s disease mouse model : A Comparative study with donepezil

“…On the other hand, inflammatory gene expression increase (Ιλ-1β, Ιλ-6, and Ccl12 ) was observed after treatment with I2-IR ligand LSL60101 but not with donepezil. Interestingly, this is further supported by a significant upregulation of Trem2 gene expression determined in the LSL60101 treated mice, further confirming the neuroinflammatory modulation by I2-IR ligand LSL60101(Hwang et al, 2010;Griñán-Ferré et al, 2019;Vasilopoulou et al, 2020a). Furthermore, increased Trem2 expression has been shown to reprogram microglia responsivity mediating microglial cytokine release, migration and clearance of Aβ deposits, ameliorating neuropathological and behavioural deficits of AD mouse models(Lee et al, 2018;Zhao et al, 2018).…”

Microarray Analysis Revealed Inflammatory Transcriptomic Changes after LSL60101 Treatment in 5XFAD Mice Model

“…In vitro studies corroborate that I2-IR ligands exert their action on the glial cells by suppressing astrocytic activation induced by lipopolysaccharide (LPS) and decreasing TNF-α levels [ 13 ]. Consistent with these changes, the recently described I2-IR ligands MCR5 and B06 decrease the expression of proinflammatory markers, such as TNF-α, IL-1β and interleukin 6 (IL-6), and promote synaptic plasticity in a mouse model of aging and neurodegeneration [ 14 , 15 , 16 ]. Interestingly, I2-IR have been found dysregulated in patients with neurodegenerative diseases, such as Alzheimer’s disease (AD) [ 17 , 18 ].…”

“…Of note, activation of the NF-κβ pathway is closely related to neurodegeneration and particularly to AD [ 35 ], while its inhibition has been shown to improve cognitive deficits in in vivo models of AD [ 49 ]. In turn, reductions in NF-κβ-regulated genes, such as Il-1β , Cox2 and Tnf-α , were observed after treatments with selective I2-IR ligands, delivering neuroprotection in mouse models of aging neurodegeneration and AD [ 14 , 15 , 16 , 39 ]. Therefore, downregulation of the NF-κβ pathway by LSL60101 might partially account for the altered gene expression of inflammatory markers and further explain its neuroprotective effect in this AD mouse model.…”