Acs Chem Neurosci
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Comparative Study
Comparison of Therapeutic Effects of TREK1 Blockers and Fluoxetine on Chronic Unpredicted Mild Stress Sensitive Rats.
The animal model for depressive behavior due to chronic unpredicted mild stress (CUMS) is commonly used to evaluate antidepressant treatments. The CUMS model has faced some criticism because of the heterogeneity of behavioral effects. Spadin and SID1900 are TREK1 blockers with a quick antidepressant effect. ⋯ This study underlines the importance of model validation by determination of CUMS sensitivity. The TREK1 blockers were found to have an effect that was more rapid and more pronounced than that of fluoxetine. Therapeutic benefits after chronic administration were associated with a restoration of impaired neurogenesis.
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Selective activation of the M1 subtype of muscarinic acetylcholine receptor, via positive allosteric modulation (PAM), is an exciting strategy to improve cognition in schizophrenia and Alzheimer's disease patients. However, highly potent M1 ago-PAMs, such as MK-7622, PF-06764427, and PF-06827443, can engender excessive activation of M1, leading to agonist actions in the prefrontal cortex (PFC) that impair cognitive function, induce behavioral convulsions, and result in other classic cholinergic adverse events (AEs). Here, we report a fundamentally new and highly selective M1 PAM, VU0486846. ⋯ Importantly, we show for the first time that an M1 PAM can reverse the cognitive deficits induced by atypical antipsychotics, such as risperidone. These findings further strengthen the argument that compounds with modest in vitro M1 PAM activity (EC50 > 100 nM) and pure-PAM activity in native tissues display robust procognitive efficacy without AEs mediated by excessive activation of M1. Overall, the combination of compound assessment with recombinant in vitro assays (mindful of receptor reserve), native tissue systems (PFC), and phenotypic screens (behavioral convulsions) is essential to fully understand and evaluate lead compounds and enhance success in clinical development.
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Positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have attracted intense interest as an exciting new approach for improving the cognitive deficits in schizophrenia and Alzheimer's disease. Recent evidence suggests that the presence of intrinsic agonist activity of some M1 PAMs may reduce efficacy and contribute to adverse effect liability. ⋯ Furthermore, PF-06827443 is an agonist in native tissue preparations and induces behavioral convulsions in mice similar to other ago-PAMs. These findings suggest that PF-06827443 is a robust ago-PAM, independent of species, in cell lines and native systems.
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The excessive accumulation of iron in deep gray structures is an important pathological characteristic in patients with Alzheimer's disease (AD). Quantitative susceptibility mapping (QSM) is more specific than other imaging-based iron measurement modalities and allows noninvasive assessment of tissue magnetic susceptibility, which has been shown to correlate well with brain iron levels. This study aimed to investigate the correlations between the magnetic susceptibility values of deep gray matter nuclei and the cognitive functions assessed by mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) in patients with mild and moderate AD. ⋯ In contrast, bilateral Rn had significantly lower susceptibility values in AD than the controls. Regardless of gender and age, the increase of magnetic susceptibility in the left Cd was significantly correlated with the decrease of MMSE scores and MoCA scores ( P < 0.05). Our study indicated that magnetic susceptibility value of left Cd could be potentially used as a biomarker of disease severity in mild and moderate AD.
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The lower efficacy of opioids in neuropathic pain may be due to the increased activity of pronociceptive systems such as substance P. We present evidence to support this hypothesis in this work from the spinal cord in a neuropathic pain model in mice. Biochemical analysis confirmed the elevated mRNA and protein level of pronociceptive substance P, the major endogenous ligand of the neurokinin-1 (NK1) receptor, in the lumbar spinal cord of chronic constriction injury (CCI)-mice. ⋯ In naive mice, the single pharmacophore opioid parent compounds provided better analgesic results, as compared to the hybrids (max 70% MPE), raising the acute pain threshold close to 100% MPE. On the other hand, the opioid parents gave poor analgesic effects under neuropathic pain conditions, while the best hybrid delivered robust (close to 100% MPE) and long lasting alleviation of both tactile and thermal hypersensitivity. The results presented emphasize the potential of opioid/NK1 hybrids in view of analgesia under nerve injury conditions.