I2 imidazoline receptor modulation protects aged SAMP8 mice against cognitive decline by suppressing the calcineurin pathway

Abstract

Brain aging and dementia are current problems that must be solved. The levels of imidazoline 2 receptors (I2-IRs) are increased in the brain in Alzheimer's disease (AD) and other neurodegenerative diseases. We tested the action of the specific and selective I2-IR ligand B06 in a mouse model of accelerated aging and AD, the senescence-accelerated mouse prone 8 (SAMP8) model. Oral administration of B06 for four weeks improved SAMP8 mouse behavior and cognition and reduced AD hallmarks, oxidative stress, and apoptotic and neuroinflammation markers. Likewise, B06 regulated glial excitatory amino acid transporter 2 and N-methyl-D aspartate 2A and 2B receptor subunit protein levels.Calcineurin (CaN) is a phosphatase that controls the phosphorylation levels of cAMP response element-binding (CREB), apoptotic mediator BCL-2-associated agonist of cell death (BAD) and GSK3β, among other molecules. Interestingly, B06 was able to reduce the levels of the CaN active form (CaN A). Likewise, CREB phosphorylation, BAD gene expression, and other factors were modified after B06 treatment. Moreover, phosphorylation of a target of CaN, nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1), was increased in B06-treated mice, impeding the transcription of genes related to neuroinflammation and neural plasticity. In summary, this I2 imidazoline ligand can exert its beneficial effects on age-related conditions by modulating CaN pathway action and affecting several molecular pathways, playing a neuroprotective role in SAMP8 mice. Table 1. Antibodies used in Western blot studies.

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

“…Recently, we reported that the amyloidogenic amyloid precursor protein processing pathway was suppressed in senescence‐accelerated mouse prone 8 and 5XFAD mice after treatment with novel I 2 ligands, anticipating the role of I 2 modulation in the amyloid‐β biogenesis (Abás et al, 2020;Griñán‐Ferré et al, 2019; Vasilopoulou, Griñán‐Ferré, et al, 2020). Accordingly, in this study, we demonstrated for the first time that chronic low‐dose treatment with I 2 ligand LSL60101 attenuated the amyloid plaque burden in 5XFAD mice.…”

“…Surprisingly, the p‐Tau reduction reached significance in the 5XFAD mice treated with the combination of LSL60101 with donepezil demonstrating, in this case, a putative additive effect of the drugs on tau pathology. Indeed, amelioration of tau pathology has been induced in AD animal models both by donepezil (Yoshiyama et al, 2010) and by I 2 ligand treatments (Griñán‐Ferré et al, 2019; Vasilopoulou, Griñán‐Ferré, et al, 2020). It is possible that the activation of distinct molecular pathways by the two molecules with different modes of actions resulted in a remarkable p‐Tau reduction observed in the donepezil/LSL60101‐treated mice group.…”

“…Most notably, the density of I 2 receptors was found to increase in AD patients (Garcia‐Sevilla et al, 1998). Several lines of evidence provided by our group demonstrated that selective I 2 ligands protected against cognitive impairment and ameliorated AD pathological features related to amyloid precursor protein processing, tau hyperphosphorylation, neuroinflammation and oxidative stress processes, using well‐established AD animal models (Abás et al, 2017, 2020; Griñán‐Ferré et al, 2019; Vasilopoulou, Griñán‐Ferré, et al, 2020). Likewise, agmatine, the proposed endogenous ligand for I 2 receptors, prevented cognitive deficits in amyloid‐β 1–42 peptide‐injected mice and of note, its effect was augmented and attenuated by I 2 agonists and antagonists, respectively (Kotagale et al, 2020).…”

LRRK2-NFATc2 Pathway Associated with Neuroinflammation May Be a Potential Therapeutic Target for Parkinson’s Disease

“… 23 Additionally, phosphorylation of NFATc1 is closely related to the transcription of genes associated with neuroinflammation in AD mice. 24 Notably, the NFATc2 isoform was the most highly expressed in murine microglia cultures, and the ability of the microglia to secrete cytokines was attenuated by deletion of NFATc2 in mouse models of AD. 25 The above findings are strong evidence to support the hypothesis that LRRK2 and NFATc2 selectively modulate pro-inflammatory cytokine expression in extracellular α-synuclein-mediated microglia via TLR2 signaling pathway.…”

Benzofuranyl-2-imidazoles as imidazoline I2 receptor ligands for Alzheimer's disease

“…Selective 2-BFI [31] decreased OS and altered the levels of antioxidant enzymes in an AD rat model and protected against OSinduced astrocytic cell death. Moreover, our group reported decreased levels of hydrogen peroxide levels and OS markers induced by two new I 2 -IR ligands in aged SAMP8 mice [32].…”