Chlorogenic Acid and Mental Diseases: From Chemistry to Medicine
Several studies have been performed using animals and human cell lines as models for assessing the protective effects of the chlorogenic acid against oxidative damage in brain tissue. The antioxidant effects of chlorogenic acid have also been reported in rats , mice and rabbits . Oboh and collaborators observed that chlorogenic acid reduces oxidative stress induced by Fe2+ and by sodium nitroprusside in a dose dependent manner. The reduction of ROS production and the inhibition of DNA fragmentation and caspase-3 cleavage have also been reported in PC12 cells following incubation with chlorogenic acid .
In contrast, a previous study has shown that chlorogenic acid (100 ng/ml) increases astrocyte viability in cultured cells, but has no direct effect on hydrogen peroxide toxicity in astrocytes. Apart from the free-radical scavenging properties of chlorogenic acid, antioxidant effects have been attributed to the increased expression of neuroprotective ribosomal proteins (PEP-1-rpS3) . Differences in the methodological procedures of different studies may be responsible for the variability of the results reported in the literature.
Despite its antioxidant effects, chlorogenic acid may also inhibit apoptotic processes. For instance, proteins from the B-cell lymphoma 2 (Bcl-2) family act as antiapoptotic molecules, and the inhibition of Bcl-XL by hydrogen peroxide was found to be strongly reduced following pretreatment with chlorogenic acid .
It is well known that ROS can activate protein kinase cascades . Cho and collaborators observed that pretreatment with chlorogenic acid stimulated JNK and p38 MAPK activation in the PC12 cell line.
A study using a human neuroblastoma cell line (MC65) revealed diminished cell viability when cells were treated with β-amyloid proteins (which form the typical extracellular plaques of AD). However, this effect can be prevented by pretreatment with chlorogenic acid. This induces an overexpression of the glycolytic enzyme phosphoglycerate kinase-1, which is associated with ATP production and regulation of neuronal apoptosis [99]. This study agrees with another study conducted using the extracts derived from the plant Centella asiatica, which has a high content of chlorogenic acid .
PC12 is a useful cell line used to monitor the expression levels of α-synuclein, a pathogenic molecule that induces the overexpression of Parkinson genes and the loss of dopaminergic neurons. Pretreatment with of PC12 cells with chlorogenic acid induces a protective effect against toxicity induced by α-synuclein. Incubation with chlorogenic acid provides protection against oxidative stress which, leads to increased cell viability. In addition, negative effects caused by the oxidized forms of dopamine, and α-synuclein were inhibited by chlorogenic acid .
Chlorogenic acid has been shown to induce neuro-protection in rat brain homogenates by lowering the activities of acetylcholinesterase and butyrylcholinesterase. These enzymatic activities are increased in neuro-degenerative diseases such as AD. Inhibition of these enzymatic activities can result in increased levels of acetylcholine in the synapses leading to an increased communication between neurons
chlorogenic acid. In view of this, it may be difficult to make a clear decision about its clinical efficacy and to ascertain the most effective therapeutic dose for the treatment and management of diseases of the central nervous system. We recommend that future studies should focus on ascertaining (1) the bioavailability and metabolisms of chlorogenic acid; (2) molecular pathways underlying the neuroprotective effects of chlorogenic acid; (3) toxicological studies to determine the maximum non-fatal doses of chlorogenic acid; and finally (4) clinical studies to examine the efficacy of chlorogenic acid in cognitively impaired humans.
Ability to Cross the Blood-brain Barrier
It has been reported that chlorogenic acid or its metabolites may cross the blood-brain barrier and exert neuroprotective effects on brain tissue . Decaffeinated coffee enriched with chlorogenic acid was administered to 39 healthy older participants, which reported positive effects on mood and cognition, including diminished headaches, and lower mental fatigue in older adults. Similar results were found on mood in 60 healthy individuals following the ingestion of chlorogenic acid. However, no improvement was reported in some mood and cognitive function assessments .
Antioxidant Effects in the Brain
Antiapoptotic Effects
Effects on Signaling Cascade
Antiamyloidogenic Effects
Effects Against α-synuclein
Cognitive Effects
The effects of chlorogenic acid on cognitive performance have been investigated in senescence-accelerated-prone mice 8, by means of the Morris water maze test. Improvements in the execution of this test and diminished latency in reaching the platform were reported in mice treated with chlorogenic acid, compared to control animals . Chlorogenic acid can also protect against anxiolytic and depressive processes by means of reducing the oxidative status in a mouse model .
Cholinergic Effects
Protective Effects Against Ischemia
In another study of focal cerebral ischemia in rats, animals were treated with different doses of chlorogenic acid in order to assess its potential neuroprotective effects against ischemia. The authors reported that the treated animals had lower brain infarction than the control rats. Moreover, sensory-motor function was improved by the high dose used (30 mg/kg i.p.). Additionally, chlorogenic acid treatment was found to reduce the pressure and compression on brain tissue, and attenuate lipid peroxidation in the brain . Lee and others also described a reduction in lipid peroxidation levels after chlorogenic acid treatment in ischemic rats. The free radical scavenging properties of the acid and inhibition of matrix metalloproteinase 2 and 9 activities are thought to a play a role in the neuroprotective effects of chlorogenic acid. Likewise, another study showed that chlorogenic acid (100 μg/kg i.p.) increased the signal of ribosomal proteins in the hippocampus (CA1 region), and slightly protected neuronal cells in the CA1 region when transient ischemia was induced in Mongolian gerbils
CONCLUSION AND FUTURE PROSPECTS
