Experimental Pretreatment with Chlorogenic Acid Prevents Transient Ischemia-Induced Cognitive Decline and Neuronal Damage in the Hippocampus through Anti-Oxidative and Anti-Inflammatory Effects

Abstract

Chlorogenic acid (CGA), an ester of caffeic acid and quinic acid, is among the phenolic acid compounds which can be naturally found in green coffee extract and tea. CGA has been studied since it displays significant pharmacological properties. The aim of this study was to investigate the effects of CGA on cognitive function and neuroprotection including its mechanisms in the hippocampus following transient forebrain ischemia in gerbils. Memory and learning following the ischemia was investigated by eight-arm radial maze and passive avoidance tests. Neuroprotection was examined by immunohistochemistry for neuronal nuclei-specific protein and Fluoro-Jade B histofluorescence staining. For mechanisms of the neuroprotection, alterations in copper, zinc-superoxide dismutase (SOD1), SOD2 as antioxidant enzymes, dihydroethidium and 4-hydroxy-2-nonenal as indicators for oxidative stress, and anti-inflammatory cytokines (interleukin (IL)-4 and IL-13) and pro-inflammatory cytokines (tumor necrosis factor α (TNF-α) and IL-2) were examined by Western blotting and/or immunohistochemistry. As a result, pretreatment with 30 mg/kg CGA attenuated cognitive impairment and displayed a neuroprotective effect against transient forebrain ischemia (TFI). In Western blotting, the expression levels of SOD2 and IL-4 were increased due to pretreatment with CGA and, furthermore, 4-HNE production and IL-4 expressions were inhibited by CGA pretreatment. Additionally, pretreated CGA enhanced antioxidant enzymes and anti-inflammatory cytokines and, in contrast, attenuated oxidative stress and pro-inflammatory cytokine expression. Based on these results, we suggest that CGA can be a useful neuroprotective material against ischemia-reperfusion injury due to its antioxidant and anti-inflammatory efficacies.

Increased Calbindin D28k Expression via Long-Term Alternate-Day Fasting Does Not Protect against Ischemia-Reperfusion Injury: A Focus on Delayed Neuronal Death, Gliosis and Immunoglobulin G Leakage

“…Accordingly, many studies have reported the factors underlying neuroprotection against TFI. The enhanced expression of antioxidant enzymes contributes to ROS scavenging, and the elevation of anti-inflammatory cytokines triggers inflammation in ischemic brains by suppressing the expression of pro-inflammatory cytokines, and the increased levels of calcium-binding proteins attenuate excitotoxicity by buffering glutamate influx [ 28 , 29 ]. Therefore, we investigated whether an IF-mediated increase in CB expression influenced neuronal survival, reactive gliosis and BBB leakage (disruption) in the hippocampal CA1 region.…”

Neuroprotective Effects of Coffee Bioactive Compounds: A Review

“…Chlorogenic acid was also reported to ameliorate brain ischemia-induced injury in rodents. In models of cerebral ischemia/reperfusion injury, it significantly reduced mortality [ 314 ], improved neurological deficit scores [ 314 , 315 ], attenuated sensory-motor functional deficits [ 316 ], reduced infarct volume [ 314 , 315 , 316 , 317 ], suppressed CA1 pyramidal cell loss [ 318 , 319 , 320 ], decreased brain edema [ 315 , 316 , 317 ], and attenuated blood–brain barrier (BBB) damage [ 316 , 317 ]. Importantly, it was demonstrated that chlorogenic acid has a neuroprotective effect against ischemia-induced cognitive deficits.…”

“…Importantly, it was demonstrated that chlorogenic acid has a neuroprotective effect against ischemia-induced cognitive deficits. It attenuated learning and memory impairments in ischemic rats [ 315 , 319 ] and in Mongolian gerbils [ 320 ]. The protective effect of chlorogenic acid against ischemia-induced brain injury appears to be related with its ability to reduce oxidative stress, neuroinflammation, and cell apoptosis.…”

“…In rats with cerebral ischemia/reperfusion injury, chlorogenic acid dose-dependently increased the activity of SOD and GSH and suppressed ROS production, lactate dehydrogenase (LDH) release, and MDA accumulation as well as promoted the expression of Nrf2, NQO-1 and heme oxygenase 1 (HO-1) [ 315 ]. Likewise, it reduced ROS production and increased SOD2 expression in the CA1 hippocampal region of gerbils with transient global cerebral ischemia [ 320 ]. Overexpression of SOD2 (but not SOD1) was also observed in ischemic rats treated with chlorogenic acid [ 319 ].…”

“…Overexpression of SOD2 (but not SOD1) was also observed in ischemic rats treated with chlorogenic acid [ 319 ]. Furthermore, chlorogenic acid suppressed the ischemia-induced increase in pro-inflammatory cytokines, i.e., TNF-α [ 317 , 320 ] and IL-2 [ 320 ], as well as overexpression of anti-inflammatory cytokines IL-4 and IL-13 [ 320 ]. It also downregulated the expression of an apoptotic marker–caspase-3 [ 315 , 317 ] and increased the expression of an anti-apoptotic protein–Bcl2 in ischemic animals [ 319 ].…”