Amelioration of BPSD-Like Phenotype and Cognitive Decline in SAMP8 Mice Model Accompanied by Molecular Changes after Treatment with I<sub>2</sub>-Imidazoline Receptor Ligand MCR5
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. I<sub>2</sub>-imidazoline receptors (I<sub>2</sub>-IRs) have been associated with neuropsyc...
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MDPI AG
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| Online Access: | https://www.mdpi.com/1999-4923/12/5/475 |
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| author | Foteini Vasilopoulou Andrea Bagan Sergio Rodriguez-Arevalo Carmen Escolano Christian Griñán-Ferré Mercè Pallàs |
| author_facet | Foteini Vasilopoulou Andrea Bagan Sergio Rodriguez-Arevalo Carmen Escolano Christian Griñán-Ferré Mercè Pallàs |
| author_sort | Foteini Vasilopoulou |
| collection | DOAJ |
| description | 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. I<sub>2</sub>-imidazoline receptors (I<sub>2</sub>-IRs) have been associated with neuropsychiatric and neurodegenerative disorders, further, I<sub>2</sub>-IR ligands have demonstrated a neuroprotective role in the central nervous system (CNS). In this study, we assessed the effect of the I<sub>2</sub>-IR ligand MCR5 on both cognitive and non-cognitive symptoms in the Senescence accelerated mice prone 8 (SAMP8) mouse model. Oral administration of I<sub>2</sub>-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 I<sub>2</sub>-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 <i>Tumor necrosis factor-alpha (Tnf-α), Interleukin 1β (Il-1β), Interleukin 6 (Il-6),</i> 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 I<sub>2</sub>-IR ligands as therapeutic agents in age-related BPSD and cognitive alterations. |
| first_indexed | 2024-03-10T19:38:56Z |
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| spelling | doaj.art-b50f4266318b4b06bdd668b207879a8e2023-11-20T01:29:11ZengMDPI AGPharmaceutics1999-49232020-05-0112547510.3390/pharmaceutics12050475Amelioration of BPSD-Like Phenotype and Cognitive Decline in SAMP8 Mice Model Accompanied by Molecular Changes after Treatment with I<sub>2</sub>-Imidazoline Receptor Ligand MCR5Foteini Vasilopoulou0Andrea Bagan1Sergio Rodriguez-Arevalo2Carmen Escolano3Christian Griñán-Ferré4Mercè Pallàs5Pharmacology Section, Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institut de Neurociències, University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, SpainLaboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, SpainLaboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, SpainLaboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, SpainPharmacology Section, Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institut de Neurociències, University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, SpainPharmacology Section, Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institut de Neurociències, University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, SpainBehavioural and psychological symptoms of dementia (BPSD), including fear-anxiety- and depressive-like behaviour, are present in Alzheimer’s disease (AD), together with memory decline. I<sub>2</sub>-imidazoline receptors (I<sub>2</sub>-IRs) have been associated with neuropsychiatric and neurodegenerative disorders, further, I<sub>2</sub>-IR ligands have demonstrated a neuroprotective role in the central nervous system (CNS). In this study, we assessed the effect of the I<sub>2</sub>-IR ligand MCR5 on both cognitive and non-cognitive symptoms in the Senescence accelerated mice prone 8 (SAMP8) mouse model. Oral administration of I<sub>2</sub>-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 I<sub>2</sub>-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 <i>Tumor necrosis factor-alpha (Tnf-α), Interleukin 1β (Il-1β), Interleukin 6 (Il-6),</i> 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 I<sub>2</sub>-IR ligands as therapeutic agents in age-related BPSD and cognitive alterations.https://www.mdpi.com/1999-4923/12/5/475I<sub>2</sub>-imidazoline receptorsBehavioural and psychological symptoms of dementia (BPSD)brain-derived neurotrophic factor (BDNF)neuroinflammationage |
| spellingShingle | Foteini Vasilopoulou Andrea Bagan Sergio Rodriguez-Arevalo Carmen Escolano Christian Griñán-Ferré Mercè Pallàs Amelioration of BPSD-Like Phenotype and Cognitive Decline in SAMP8 Mice Model Accompanied by Molecular Changes after Treatment with I<sub>2</sub>-Imidazoline Receptor Ligand MCR5 Pharmaceutics I<sub>2</sub>-imidazoline receptors Behavioural and psychological symptoms of dementia (BPSD) brain-derived neurotrophic factor (BDNF) neuroinflammation age |
| title | Amelioration of BPSD-Like Phenotype and Cognitive Decline in SAMP8 Mice Model Accompanied by Molecular Changes after Treatment with I<sub>2</sub>-Imidazoline Receptor Ligand MCR5 |
| title_full | Amelioration of BPSD-Like Phenotype and Cognitive Decline in SAMP8 Mice Model Accompanied by Molecular Changes after Treatment with I<sub>2</sub>-Imidazoline Receptor Ligand MCR5 |
| title_fullStr | Amelioration of BPSD-Like Phenotype and Cognitive Decline in SAMP8 Mice Model Accompanied by Molecular Changes after Treatment with I<sub>2</sub>-Imidazoline Receptor Ligand MCR5 |
| title_full_unstemmed | Amelioration of BPSD-Like Phenotype and Cognitive Decline in SAMP8 Mice Model Accompanied by Molecular Changes after Treatment with I<sub>2</sub>-Imidazoline Receptor Ligand MCR5 |
| title_short | Amelioration of BPSD-Like Phenotype and Cognitive Decline in SAMP8 Mice Model Accompanied by Molecular Changes after Treatment with I<sub>2</sub>-Imidazoline Receptor Ligand MCR5 |
| title_sort | amelioration of bpsd like phenotype and cognitive decline in samp8 mice model accompanied by molecular changes after treatment with i sub 2 sub imidazoline receptor ligand mcr5 |
| topic | I<sub>2</sub>-imidazoline receptors Behavioural and psychological symptoms of dementia (BPSD) brain-derived neurotrophic factor (BDNF) neuroinflammation age |
| url | https://www.mdpi.com/1999-4923/12/5/475 |
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