The role of curcumin in ameliorating learning and memory disorders

Curcumin is an active yellow substance extracted from the rhizome of Curcuma longa (turmeric). In recent years, curcumin has been reported to have anti-cancer, liver protection, thrombus inhibitor, cardiovascular and anti-arthritis effects. Curcumin has been also known to modulate intracellular signaling pathways that control cell growth, inflammation, and apoptosis (programmed cell death). Curcumin is a powerful antioxidant that reduces circulating free radicals and due to its antioxidant and anti-inflammatory activities can be a potential candidate for the prevention or treatment of neurological diseases and memory disorders. The results of studies in rodents (without induction of memory impairment) have shown that certain doses of curcumin improve memory function. It has been reported that curcumin can prevent and improve age-related memory impairment as one of the causes of irreversible memory impairment over time. However, the results of some studies have shown that in the absence of memory impairment, the effect of curcumin is similar to placebo and does not increase learning and memory. Since the identification of basic and potential mechanisms involved in memory enhancement for therapeutic use of this composition is very important, this article has been reviewed the role of curcumin in improving memory disorders as well as the involved molecular mechanisms. A summary of these mechanisms are outlined below:•• Modifying monoamines (serotonin, dopamine, and noradrenaline) levels, monoamine oxidase (MAO) activity, acetylcholine-esterase activity, and glutamate release. Animal studies have shown that curcumin inhibits low levels of monoamine oxidase A (MAO-A) in the brain, increasing serotonin and noradrenaline levels, and in high doses inhibits dopamine metabolism by inhibiting MAO-B enzyme. Biochemical studies have also shown that curcumin significantly increases serotonin and noradrenaline levels in both the frontal cortex and hippocampus. Studies have also shown that curcumin is effective in reducing cellular reactive oxygen species due to increasing glutamate levels. On the other hand, in the neuronal terminals of the hippocampus, curcumin can reduce the concentration of calcium in the synaptosomes, so this effect is the same as nimodipine as an L-type calcium channel blocker, and thus prevent the neurotoxicity caused by the influx of calcium into the cell. Also, curcumin plays a role in modulating muscarinic receptors. Moreover, studies have shown that curcumin treatment significantly increases acetylcholine-transferase and regulates acetylcholine-esterase expression which has a positive effect on cognitive function. •• Providing neuroprotection and enhances neuronal growth by influencing brain-derived neurotrophic factor (BDNF) levels, cyclic adenosine monophosphate (cAMP) activity, and extracellular signal-regulated kinase (ERK) activity. Increased BDNF plays an important role in brain growth and synaptic plasticity by inhibiting nerve damage and stimulating neurogenesis and cell survival. BDNF / tyrosine kinase B signaling re-leads to phosphorylation and activation of transcription factors such as CREB, which results in long-term gene expression and synaptic changes. In one study, curcumin administration significantly increased the expression of phosphorylated BDNF in the dentate gyrus. Another study showed that curcumin use in rats increased hippocampal neurogenesis by regulating and activating BDNF and 5-HT1A receptors. By activating BDNF, curcumin protects nerve cells from chronic stress and glutamate over-stimulation. In another study, long-term administration of curcumin showed a steady increase in BDNF levels in the amygdala and increased phosphorylation of ERK (Extracellular signal-regulated kinases). ERK1/2 phosphorylation has been shown to activate a set of protein signaling cascades, which in turn leads to a wide variety of cellular processes such as growth, survival, and neuronal cell formation. Activation of ERK signaling pathways leads to phosphorylation of CREB as a major mediator of cell function, survival, and differentiation. Besides, activation of CREB, in turn, leads to increase BDNF gene expression. Zhang et al. (2012) showed that the level of phosphorylated ERK proteins in the amygdala increased rapidly in curcumin-treated animals. •• Protecting against oxidative stress through activation of antioxidant enzymes, inhibition of lipid peroxidation, metal ion chelation and increasing inducible nitric oxide synthase activity. Glutathione peroxidase (GPx) and superoxide dismutase (SOD) are the most important antioxidant enzymes that protect against reactive oxygen species (ROS). Curcumin increases the activity of SOD, GPx, and GR enzymes and inhibits the increase of Malondialdehyde (MDA) in a dose-dependent manner which indicates the antioxidant effects of this substance. Moreover, curcumin can reduce beta-oxidation of fatty acids and lipid peroxidation in brain tissue, and given that the intensification of oxidation of such substances can impair learning and memory, so part of the beneficial effect of high-dose curcumin on learning and memory can be attributed to the inhibition of fatty acid oxidation. Studies have also shown that curcumin has a protective effect against damage caused by metal ions such as iron, lead, and cadmium in rat hippocampal cells by chelating them and, thus reducing their neurotoxicity. Studies have shown that increasing nitric oxide (NO) and activating the nNOS/NO signaling pathway in the rat hippocampus improves memory while inhibiting it with nNOS-specific inhibitors reduces it. Neurological, chemical, and behavioral evidence suggests that pretreatment with curcumin significantly increases nNOS/NO pathway activity in the peripheral cortex (PFC), amygdala, and hippocampus and thus improves memory in mice. On the other hand, 7-nitroimidazole (7-NI), a specific inhibitor of nNOS, reduces the effect of curcumin on improving long-term memory. •• Modulating inflammation by influencing cytokine gene expression, nuclear factor-κB (NF-κB) activity, tumor necrosis factor-α (TNF-α) levels. It has been observed that microglia, as the main immune cells in the CNS, can produce inflammatory cytokines to regulate homeostasis and fight pathogens. Overproduction of inflammatory cytokines can lead to neuritis, nerve damage and death. In addition, neuroinflammation is the first major step in neurodegenerative diseases. Curcumin inhibits and reduces the production of inflammatory factors by inhibiting microglia activation. Curcumin exerts its anti-inflammatory effect by inhibiting NF-ƙB activation. Curcumin also reduces and modulates the enzyme COX-2, various inflammatory cytokines such as TNFα, IL-1, IL-6, IL-8 and interferon γ. Conclusion There is a lot of evidence that curcumin can play a role in the treatment of neurological diseases such as Alzheimer's, depression, and Parkinson's. Numerous studies have also shown that curcumin has a significant effect on improving learning and memory in various laboratory models and can play a preventive and therapeutic role in this regard. This may be due to its known antioxidant and anti-inflammatory properties, as well as the modulation of neurotransmitters or the regulation of homeostasis of proteins involved in signaling pathways. Although the use of curcumin seems safe according to the results of laboratory studies and clinical trials, it is necessary to prove the effectiveness and safety of curcumin in its short-term and long-term use in clinical trials to improve learning and memory.