Cyclic peptidomimetic for the treatment of neurological disorders
a peptidomimetic and neurodegenerative disease technology, applied in the direction of peptides, nerve disorders, drug compositions, etc., can solve the problems of severe limitations in clinical potential, and achieve the effects of reducing the expression of bdnf, and increasing monoaminergic signaling
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example 1
Antidepressant Effects of CN2097
[0091]Depressive symptomatology has been reliably characterized using exogenous corticosterone (CORT) administration, e.g., dendritic atrophy in hippocampal pyramidal cells with loss of CA3 and CA1 apical dendrites.39 Importantly, CORT administration leads to impaired BDNF-mediated signaling and synaptic plasticity in limbic and forebrain regions. In this model, ketamine, which is known to be effective for the treatment of TRD, significantly reduced depressive-like behavior.40
[0092]We hypothesize that antidepressant-like effects of ketamine and CN2097 are mediated via the same signaling pathways, e.g., by the activation of mTOR. The effects of i.v. CN2097 on the depressive-like behavior of repeated corticosterone-injected mice were examined in the Chronic mild stress (CMS) animal model, which comprise both physical and social stressors.41
[0093]Mice were divided into two groups, namely, control (Ctrl) and CORT. The mice in the CORT group were injecte...
example 2
CN2097 Reverses Behavioral Alterations Induced in the CMS Model
[0098]To further test CN2097, we used the Chronic Mild Stress (CMS) model which has been shown to evoke anxiety and lower sucrose consumption (postulated to reflect anhedonia), symptoms associated with MDD. As described in Marshall (2018),44 mice subjected to repeated daily stress for 3 weeks, then received a single injection of CN2097 (10 mg / kg) or vehicle.
[0099]The acute effects of CN2097 on anxiety were evaluated by the elevated plus-maze (EPM) and novelty-suppressed feeding (NSF) tests. As shown in FIG. 4 (left panel), CN2097 increased the time spent in open arms in the EPM.
[0100]In the NSF test, anxiety-induced hypophagia was assessed by measuring the latency of mice to eat a familiar food in an aversive environment. As shown in FIG. 4 (right panel), the administration of CN2097 1 hour prior to testing significantly shortened the latency period until feeding. These data suggest that CN2097 effectively reverses behav...
example 3
Antidepressant Effects of CN2097 and dR7-2097
[0102]The discovery of rapidly acting antidepressants, such as ketamine, has transformed our ideas about depression treatment. Based on the above-described data (FIGS. 2-4), CN2097 elicits rapid antidepressant effects that merits further testing. Moreover, although dR7-2097 is a stable analog that is not cleared rapidly like CN2097, its functional efficacy remains to be determined and compared to CN2097 in an animal model of depression. Accordingly, the effects of CN2097 and dR7-2097 on memory recall were assessed in the Contextual Fear Conditioning (CFC) test.47
[0103]Mice received i.p. injections of 1, 5, or 10 mg / kg CN2097 or 1 or 5 mg / kg dR7-2097.
[0104]As shown in the FIG. 5, dR7-2097 was more efficacious than CN2097 in significantly increasing memory recall in the CFC test. These results show that it is possible to modify CN2097 with (D)-amino acids and not only maintain the efficacy but enhance it. The suggests that the increased st...
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