Neuromodulation and neuroprotective effects of chlorogenic acids in excitatory synapses of mouse hippocampal slices

Abstract

The increased healthspan afforded by coffee intake provides novel opportunities to identify new therapeutic strategies. Caffeine has been proposed to afford benefits through adenosine A2A receptors, which can control synaptic dysfunction underlying some brain disease. However, decaffeinated coffee and other main components of coffee such as chlorogenic acids, also attenuate brain dysfunction, although it is unknown if they control synaptic function. We now used electrophysiological recordings in mouse hippocampal slices to test if realistic concentrations of chlorogenic acids directly affect synaptic transmission and plasticity. 3-(3,4-dihydroxycinnamoyl)quinic acid (CA, 1–10 μM) and 5-O-(trans-3,4-dihydroxycinnamoyl)-D-quinic acid (NCA, 1–10 μM) were devoid of effect on synaptic transmission, paired-pulse facilitation or long-term potentiation (LTP) and long-term depression (LTD) in Schaffer collaterals-CA1 pyramidal synapses. However, CA and NCA increased the recovery of synaptic transmission upon re-oxygenation following 7 min of oxygen/glucose deprivation, an in vitro ischemia model. Also, CA and NCA attenuated the shift of LTD into LTP observed in hippocampal slices from animals with hippocampal-dependent memory deterioration after exposure to β-amyloid 1–42 (2 nmol, icv), in the context of Alzheimer’s disease. These findings show that chlorogenic acids do not directly affect synaptic transmission and plasticity but can indirectly affect other cellular targets to correct synaptic dysfunction. Unraveling the molecular mechanisms of action of chlorogenic acids will allow the design of hitherto unrecognized novel neuroprotective strategies.

Chlorogenic Acid Decreases Glutamate Release from Rat Cortical Nerve Terminals by P/Q-Type Ca2+ Channel Suppression: A Possible Neuroprotective Mechanism

“…These KA-induced alterations were significantly counteracted by CGA pretreatment, indicating that CGA exerts anti-excitotoxic and neuroprotective effects. Our results are in accordance with those of previous studies, which have investigated the neuroprotective effects of CGA by using in vitro and in vivo experimental models and concluded that CGA protects neurons from glutamate-induced death [ 21 , 24 , 25 , 35 ]. Because the abnormal release of glutamate leading to neuronal loss is a mechanism underlying numerous neurological diseases [ 44 ], inhibiting glutamate release is a key strategy for neuroprotection against excitotoxicity [ 5 , 6 , 7 ].…”

“…CGA did not affect the basal glutamate release; however, when the synaptosomes were depolarized with 4-AP, CGA inhibited glutamate release, suggesting that CGA reduces the release of glutamate triggered by neuronal activation. This result is consistent with those of electrophysiological studies, which have demonstrated that CGA exerts no significant effects on synaptic transmission or synaptic plasticity under physiological conditions but can mitigate the deterioration of synaptic function in pathological conditions [ 35 ].…”

Structural Investigation of the Interaction Mechanism between Chlorogenic Acid and AMPA Receptor via In Silico Approaches

“…CGA has a variety of biological activities, including anti-inflammatory, analgesic, and neuroprotection activities [ 38 , 39 ]. Previous experiments have shown that CGA can significantly relieve chronic pain by inhibiting GluA1 and affecting synaptic plasticity [ 40 ]. However, the molecular mechanism by which CGA acts on GluA1 remains elusive and further research is needed.…”

Chlorogenic Acid Ameliorates High-Fat and High-Fructose Diet-Induced Cognitive Impairment via Mediating the Microbiota–Gut–Brain Axis

“…24 Notably, CGA reduced synaptic dysfunction by increasing synaptic transmission or inhibiting the abnormal transformation of hippocampal plasticity. 25 The CGA intake also prevented cognitive deficits and reduced Aβ plaque deposition via disaggregation of Aβ. 26 Therefore, we hypothesize that gut microbiota and its metabolites may be involved in improving cognitive dysfunction by CGA.…”

“…The supplementation of CGA has improved metabolic syndrome, nonalcoholic fatty liver, and type 2 diabetes mellitus. , For example, CGA improved liver lobular inflammation by increasing the percentages of Blautia and Coprococcus in the Firmicutes phylum and improving the plasma SCFA profile in TSOD mice, a spontaneous mouse model of metabolic syndrome . Notably, CGA reduced synaptic dysfunction by increasing synaptic transmission or inhibiting the abnormal transformation of hippocampal plasticity . The CGA intake also prevented cognitive deficits and reduced Aβ plaque deposition via disaggregation of Aβ .…”