Full Length ArticleEffect of caffeine, caffeic acid and their various combinations on enzymes of cholinergic, monoaminergic and purinergic systems critical to neurodegeneration in rat brain—In vitro
Introduction
Caffeine is a well-known plant alkaloid found in leaves, seeds and nuts of a number of plants. It is a major constituent of coffee, cocoa, tea, cola drinks and chocolate. Caffeine is a central nervous system (CNS) stimulant that belongs to the methylxanthine class (Ding et al., 2014), and most widely consumed psychoactive food bioactive compound in the world (Nehlig et al., 1992). Research has shown that caffeine can induces a broad spectrum of cellular and pharmacological effects, including central nervous system (CNS) stimulation (Fredholm et al., 1999), potential cognitive enhancement properties (Abreu et al., 2011), and antioxidant properties (Noschang et al., 2009, Shi et al., 1991), among others. Evidence suggests that in humans, there is a relationship between chronic coffee/caffeine consumption and cognitive function (Ritchie et al., 2007, Santos et al., 2010). Acevedo et al. (2016) recently reported that caffeine exposure stimulates motor activity in the mouse spinal cord. Nevertheless, it has been reported that higher doses of caffeine induces negative effects such as anxiety, restlessness, insomnia, and tachycardia (Herz, 1999).
Caffeic acid is a natural phenolic compound found in many plants and occurs in diets as part of fruits, vegetables, tea and wine (Clifford, 1999). Clifford (2000) reported that the absorption of this compound is directly associated with the amount of coffee consumed, being able to achieve 500 to 800 mg/day in individuals with high coffee intake (Clifford, 2000). It has been reported to have broad spectrum of bioactive activities including antidiabetic, antihypertensive, antioxidant, immunomodulatory, anti-inflammatory and neuroprotective properties (Chiou et al., 2017, Chan and Ho, 1997, Tota et al., 2010, Know et al., 2010). Studies have also revealed that caffeic acid exerts a protective effect against hydrogen peroxide-induced oxidative injury in the brain (Know et al., 2010), ameliorates cerebral ischemia (Zhou et al., 2006) and protect against brain damage as well as behavioral and biochemical changes caused by aluminium-induced toxicity (Lee et al., 2007). These bioactive phytochemicals that occur naturally in plants have begun to receive much attention as safe antioxidants, since they may be used to protect humans from deleterious effect of oxidative stress (Scalbert et al., 2005). On the other hand, the use of antioxidants may reduce the progression of neuronal degeneration such as Alzheimer’s disease (AD) (Dokuyucu et al., 2016, Habtemariam, 2016).
Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are key enzymes of the cholinergic system that play critical role in the pathogenesis of neurodegenerative diseases especially Alz AD. AChE is responsible for the hydrolysis of acetylcholine at the synaptic cleft of cholinergic neurons (Lendvai and Vizi, 2008). Impairment of the cholinergic neuron have been implicated in the pathogenesis of AD and major therapeutic strategy for managing this disease involves the use of cholinesterase inhibitors (Lendvai and Vizi, 2008).
Furthermore, ecto-nucleoside triphosphate diphosphohydrolase (E-NTPase) are class of enzyme well characterized in the central nervous system (Rocha et al., 1993, Schetinger et al., 2007). It hydrolyzes ATP and ADP into nucleoside monophosphates. The importance of E-NTPDase in the tissues is related closely to the presence of purinoreceptors on the cells (Beaudoin et al., 1997). Na+/K+-ATPase is an enzyme of the plasma membrane responsible for the active transport of sodium and potassium ions in the nervous system regulating the ionic gradient of neuronal cells. The enzyme is present in high concentration in brain cellular membranes, consuming about 40–50% of the ATP generated in this tissue (Ericinska and Silver, 1994) and plays a pertinent role in brain development and function. Studies have shown that inhibition of Na+/K+ATPase activity induces the release of neurotransmitters including glutamate, which is proposed to play a major role in neuronal death after excitotoxic and ischemic insults (Lees, 1991).
Monoamine oxidases (MAOs) are an integral proteins which are found in the outer mitochondrial membrane and are responsible for the regulation and metabolism of monoamine neurotransmitters in the brain and peripheral tissues (Walker et al., 1971). One of their primary role is the regulation of the levels of biogenic amines in the brain and peripheral tissues by catalyzing their oxidative deamination. Recent studies have established that MAOs are associated with psychiatric and neurological disorders, including depression, Parkinson’s disease (PD) and AD. Inhibition of MAOs has been reported to possess therapeutic activities such as neuroprotective properties and functions as antidepressants and antianxiety agents and thus, could increase the level of neurotransmitters in the central nervous system (Saura et al., 1994).
Over the years, establishing therapeutic safe dose for caffeine has been quite challenging due to its CNS stimulatory effect and its ability to induce addiction. In lieu of this, recent research works are focusing on combining caffeine intake with other bioactive compounds with potential neuro-protective properties. This is aimed to offer a potential therapeutic synergy as well as ameliorate the possible detrimental effects that may be associated with caffeine consumption (Dorostghoal et al., 2012). Hence, this present study sought to investigate the effects of caffeine, caffeic acid and its proportional combinations on enzymes of cholinergic, monoaminergic and purinergic systems relevant to neurodegeneration in different brain structures – in vitro.
Section snippets
Chemicals and reagents
Chemicals and reagents used such as ATP, AMP, ouabain, and malachite green were procured from Sigma-Aldrich, Inc., (St Louis, MO). Trichloroacetic acid (TCA), 5,51-dithiobisnitrobenzoic acid were sourced from Sigma-Aldrich, Chemie GmbH (Steinheim, Germany); methanol, pyrocatechol and acetic acid were sourced from BDH Chemicals Ltd., (Poole, England). All other chemicals were of analytical grade while the water used for all analysis was glass distilled.
Sample preparation
The stock concentration of caffeine and
Effect of caffeine and its various combinations with caffeic acid on AChE activity
We observed in this study that caffeine and its various combinations with caffeic acid were able to inhibit the activity of AChE both in the WBMC and CC (Fig. 1a and b). It was also observed from the result that the combination of caffeine with caffeic acid resulted in antagonistic inhibitory effect on the AChE activity (P < 0.05) when compared with caffeine alone in both the WBMC and CC homogenates. However, combination of high dose of caffeic acid with caffeine resulted in decrease of AChE
Discussion
A number of food bioactive compounds have been investigated for their neuromodulatory effects. Notable among these are alkaloids and phenolic groups of phytochemicals which often exist in natural food sources in different proportions. Caffeine is an alkaloid found abundantly distributed in many foods and beverages such as coffee, tea and cocoa. Studies have shown that in coffee for example, caffeine is the most abundantly distributed alkaloid while caffeic acid is one of the predominant
Conclusion
In this study, we have been able to show that caffeine, caffeic acid and their various combinations modulate the activities of some enzymes critical to neuronal function in vitro in rat brain structures. In all, we observed that a higher proportion of caffeine to caffeic acid combination offered the highest enzyme modulatory effects. Therefore, we conclude that food rich in higher proportion of caffeine to caffeic acid could offer higher neuromodulatory effects. These effects might be of
Conflicts of interest
The authors have no conflicts of interest to declare.
Funding
This research was not funded by any grant received by any of the authors.
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