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  • Caffeic acid dihydroxycinnamic acid is

    2023-09-18

    Caffeic Aprotinin (3,4-dihydroxycinnamic acid) is a natural compound that inhibits 5-LO and exerts potent anti-inflammatory and antioxidant properties. Recently, Takeda et al. reported that caffeic acid provided neuroprotective and anti-depressive activities [23]. Sertraline, a selective serotonin reuptake inhibitor (SSRI), can improve cognitive deficits [24]. Therefore, in this study we used sertraline as a positive control and caffeic acid and 5-LO-silencer lentiviral vectors to inhibit the activities or suppress the expression of 5-LO to investigate the mechanism and effects of 5-LO on depressive behavior and learning and memory deficits in the chronic unpredictable mild stress (CUMS) rat model.
    Materials and methods
    Results
    Discussion Several studies suggest that inflammation in the CNS is associated with mood disorders and cognitive deficits. Moreover, a recent systematic review and meta-analysis suggested that anti-inflammatory treatment decreases depressive symptoms without increased risks of adverse effects [31]. Neuroinflammation in response to aversive stimuli, such as chronic mild stress, is mediated by inflammatory cytokines, chemokines, and cellular adhesion molecules. In addition, inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α, PGs, and LTs) interact with pathophysiological domains, including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and the behavioral and cognitive changes that characterize depression. Moreover, a recent study indicated that LTs act as key mediators and amplifiers in inflammation [32]. Under stimulation, cytosolic phospholipase A2 catabolizes membranes into arachidonic acid, which 5-LO converts into unstable LTA4 via 5-HPETE, using the LTA4 synthase to yield LTs, including LTB4, LTC4, and LTD4. As 5-LO is mainly recognized for its role in the formation of LTs, it appears to be a key part of the pathophysiology of inflammation [18], [33]. Recently, it has been suggested that 5-LO is present in the CNS and plays an important role in normal and pathological processes. Noguchi [34] found mRNA expression of 5-LO in the spinal microglia in a rat spared nerve injury model, and the administration of a 5-LO inhibitor or a receptor antagonist reduced mechanical allodynia through suppression of inflammation. As reported, the 5-LO pathway contributes to microglial activation and neuroinflammation and to axonal damage in cuprizone-induced demyelination [21]. Some of the neuropsychiatric literature reports that acute and chronic stress are both associated with increased production of 5-LO in the brain, and the administration of a 5-LO suppressor can relieve neuroinflammation and improve depressive behavior in animals [35], [36]. It seems impossible to separate emotion from cognition in human daily experiences, and emotional processes impact planning and problem/solving abilities as well as learning and memory [37]. Growing data suggest that depressive symptoms aggravate the risk of progression to mild cognitive impairment [38]. In addition, there is a significant association between inflammation and learning/memory deficits in neurodegeneration animal models, including models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis [39], [40], [41]. On the basis of these studies, we predicted the CUMS-treated rats would suffer from cognitive impairment, that there would be Aprotinin a strong association between inflammation and cognitive impairment, and that inhibiting the activity or expression of 5-LO would improve the learning and memory of rats. Indeed, after 6weeks of CUMS treatment, general activity and sucrose intake were noticeably decreased in rats. Furthermore, CUMS significantly increased the escape latency and decreased the number of platform crosses in the MWM test. CUMS also increased the error number and decreased the latency in the step-down-type passive avoidance test. Inhibiting the activity or the expression of 5-LO reversed the up-regulation of inflammatory cytokines and oxidative stress in the hippocampus and improved learning and memory in rats, suggesting deficits in learning and memory observed in depressed rats could be triggered by intensifying the hippocampal inflammatory response.