Methyl Jasmonate: Behavioral And Molecular Implications in Neurological DisordersⅠ

Methyl jasmonate (MJ) is a derivative of the jasmonate family which is found in most tropical regions of the world and present in many fruits and vegetables such as grapevines, tomato, rice, and sugarcane. MJ is a cyclopentanone phytohormone that plays a vital role in defense against stress and pathogens in plants. This has led to its isolation from plants for studies in animals. Many of these studies have been carried out to evaluate its therapeutic effects on behavioral and neurochemical functions. It has however been proposed to have beneficial potential over a wide range of neurological disorders. 

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Hence, this review aims to provide an overview of the neuroprotective properties of MJ and its probable mechanisms for ameliorating neurological disorders. The information used for this review was sourced from research articles and scientific databases using ‘methyl jasmonate’, ‘behavior’, ‘neuroprotection’, ‘neurodegenerative diseases’, and ‘mechanisms’ as search words. The review highlights its influences on behavioral patterns of anxiety, aggression, depression, memory, psychotic, and stress. The molecular mechanisms such as modulation of the antioxidant defense, inflammatory biomarkers, neurotransmitter regulation, and neuronal regeneration, underlying its actions in managing neurodegenerative diseases like Alzheimer’s and Parkinson’s diseases are also discussed. This review, therefore, provides a detailed evaluation of methyl jasmonate as a potential neuroprotective compound with the ability to modify behavioral and molecular biomarkers underlying neurological disorders. Hence, MJ could be modeled as a guided treatment for the management of brain diseases. 

KEY WORDS: Methyl jasmonate; Neuroprotection; Behavior; Neurodegenerative diseases; Depression; Anxiety

INTRODUCTION 

Jasmonates are cyclopentanone phytohormones that play an imperative role in the defense of plants against abiotic stressors and pathogenic invasions [1]. Although they were initially isolated from Jasminum grandiflorum L., a plant mostly found in tropical regions [2], they are extensively distributed in plants and some microorganisms [1]. They are cell regulators, known to activate intracellular signaling mechanisms in plant growth, defense, and response to stress triggers [3]. Their biosynthesis from linolenic acid in plants is analogous to the synthesis of eicosanoids from arachidonic acid in animals [3,4]. The family of jasmonates includes Cis-jasmone (CJ), Jasmonic acid (JA), and Methyl jasmonate (MJ) [3]. 

Of all the members of the Jasmonates family, MJ is the most studied. MJ is an adaptogenic phytohormone [5] released by plant cells in response to environmental stress, injury, and pathogen invasions. It induces the synthesis of proteinase inhibitor proteins, which are involved in plants’ defense against a variety of biotic and abiotic stressors [5]. On exposure of plants to stressors, MJ is synthesized, resulting in the activation of the proteinase inhibitor gene and subsequently, the expression of proteinase inhibitor proteins [5,6]. Its involvement in the adaptation of plants to stress is further supported by its increased level following plants’ exposure to stressors [5,7]. It also plays a vital role in intracellular signaling and defense in response to pathogenic invasions [1]. 

One of the numerous adaptogenic properties of MJ relies on its ability to regulate the activities of antioxidants and combat the harmful effects of oxidant molecules [8]. Jasmonates and their derivatives are widely recognized in the practice of aromatherapy for depression, tension, nervousness, anxiety, and mental alertness [5,9]. Earlier experimental studies on MJ were largely on its therapeutic potential on cancer cells that have attracted global recognition as a promising antitumor agent. The uniqueness of MJ in cancer pathology is related to its ability to preferentially kill cancer cells via several unrelated molecular mechanisms without causing damage to normal body cells. These findings have been described as inspiring evidence that may encourage its development for the treatment of cancer and other debilitating diseases that require prolonged therapy [1,5,7,10-15]. 

Meanwhile, the possibility of its potential usefulness in neuropsychiatric disorders stemmed from the reports of Hossain et al. [16], which have shown that MJ exhibited a sedative effect and enhanced GABAergic neurotransmission. These findings have led to extensive studies on the effects of MJ on neurological disorders and the mechanisms underlying its neuroprotective activity in rodents [17-23]. This review presents the documented evidence of the neuroprotective activities of MJ and the mechanisms underlying its therapeutic potential in neurological disorders. It also highlights the mechanisms by which the adaptogenic-like property of MJ could help alleviate chronic stress-induced psychopathologies.

SAFETY AND TOXICITY 

The ability of MJ to offer cellular protection has generated more attention for its potential use as a therapeutic agent in various disorders and diseases. This has led to the screening of MJ for potential toxicity by several authors [1,2,7,10,12,24,25]. In an investigation by Flescher [12], and Cohen and Flescher [1], MJ administration preferentially killed cancer cells, without affecting normal body cells. Umukoro and Olugbemide [2] also reported no case of toxicity or death in mice after administering 100− 500 mg/kg of MJ. However, results of several studies on acute toxicity, skin irritation, mucous membrane (eye) irritation, skin sensitization, phototoxicity, and photoallergy of MJ indicated that the LD50 for oral administration was ＞ 5 g/kg, and for skin use, the LD50 was ＞ 2 g/kg. Additionally, no irritation was observed in the human repeated-insult patch test and several animal studies. 

Furthermore, no irritation was detected in the mucous membrane test. Sensitization reactions in animal and human studies and photo-irritation and photoallergy studies in humans did not show any significant toxicity [25]. This finding further support previous investigations, which show that MJ is safe, as it is not toxic to normal body cells [1,7]. Likewise, the US Federal Environmental Protection Agency in 2013 issued MJ an exclusion for tolerance requirement test as it was observed to be naturally available in human nutrition [26]. The Food and Agriculture Organization/World Health Organization also approved MJ amongst other food additives [27]. MJ was also detected to have no toxic outcome in all experiments involving all drug routes [14,25].

METHYL JASMONATE MODIFIES BEHAVIORS ASSOCIATED WITH NEUROLOGICAL DISORDERS 

MJ has been implicated in various behavioral modifications, such as anxiety, depression, aggression, and memory among others, using experimental animal models. These are summarized in Figure 1 and Table 1.

Anxiety/Anxiolytic 

Activity Anxiety is a disorder of the central nervous system (CNS) associated with an imbalance between excitatory and inhibitory impulses in the brain. These imbalance areas result in decreased GABAergic and increased glutaminergic neurochemical pathways respectively [28-32]. Anxiety manifests in various ways like fear, eating disorder, worry, and suicidal tendencies in humans [22]. Several studies have explored the anti-anxiolytic potential of MJ. Most of which used mice models. Umukoro et al. [22] demonstrated the anti-anxiolytic effect of MJ on unpredictable chronic mild stress (UCMS)-induced mice while studying the explorative behavior of the mice in a light/dark transition test and elevated plus maze (EPM) test. In the EPM test, MJ reduced the frequency and extent of time spent in the closed arm in UCMS-induced mice. MJ also reduced the time spent by mice in the dark compartment in a light/dark transition test of UCMS-induced mice. All these observations suggest the anti-anxiogenic activity of MJ [22].

Depression 

Depression is a prevalent disorder that negatively impacts the quality of life worldwide. It affects about 20% of the world’s population and is typically higher in females than in males with a ratio of 5:2. Preclinical and clinical investigations have implicated serotonin and norepinephrine in its pathogenesis [33,34]. The deficiency of these monoaminergic transmitters in the brain is reported to be one of the most significant etiological factors for the cause of depression. The recurrent nature of depression and its numerous triggers have made it difficult to manage [34-36]. These have led to increased interest in researching more effective antidepressants [37,38]. 

In a study conducted by Adebesin et al. [18], an acute stress model of tail suspension test (TST) was adapted to investigate the antidepressant-like property of MJ in UCMS-induced mice. An increased latency period was observed in UCMS-induced mice. This period was significantly reduced, following treatment with MJ, indicating antidepressant-like properties [18]. This finding is consistent with that of Umukoro et al. [37] where acute stress models of TST and forced swim test (FST) were adapted in mice to study the antidepressant activity of MJ. MJ significantly decreased the period of immobility in both tests. Adebesin et al. [18] went further by using the sucrose preference test to evaluate the anti-depressant activity of MJ. This test is used to evaluate anhedonia (inability to experience pleasure), a key symptom of depression in humans. They reported that MJ attenuated impaired sucrose intake in rodents initially exposed to UCMS [18]. Biochemical evaluations have also been carried out to confirm the anti-depressant property of MJ. In a study by Zomkowski et al. [39], MJ reduced serotonin levels [39]. 

Studies have shown also that the anti-immobility exhibited by antidepressants in the FST and TST is mediated through the facilitation of both serotonergic and noradrenergic neurotransmissions [37]. Additionally, Umukoro et al. [37] employed the yohimbine lethality test to elucidate the role of monoaminergic transmitters in the antidepressant-like activity of MJ. Antidepressants are known to synergistically potentiate the lethality of yohimbine. In the study, intraperitoneal injections of MJ at doses of 25 mg/kg and 50 mg/kg, significantly increased the lethal effect of yohimbine. Yohimbine is a 2-adrenergic receptor antagonist that stimulates sympathetic centers in the brain, resulting in increased sympathetic discharge in the CNS and peripheral nervous system (PNS) [37]. Antagonism of 2-adrenergic receptors promotes the release of noradrenaline due to increased central sympathetic activity and induces serotonin release, further contributing to the overall toxicity caused by yohimbine. MJ synergistically potentiate the lethality of yohimbine by allowing more amines to get to receptors in high quantities, either by impeding their reuptake or by decreasing their inactivation, thus suggesting the involvement of monoaminergic transmitters in its antidepressant property in mice [37].

Aggression 

Aggression is a deliberate series of actions that inflict harm on another organism and is a major component of the stress-syndrome. It is characterized by low tolerance to frustration and studies have shown that feeling of frustration results from prolonged stress [40,41]. Aggression may manifest itself as a defensive or offensive behavior. Although aggression and depression are diagnostically categorized differently by the psychiatric classification systems Diagnostic and Statistical Manual of Mental Disorders 4th edition, they are however clinically and biochemically related [35,37]. The serotonergic system is implicated in both disorders [35]. This is proven by alleviated symptoms of depression and aggression when serotonin receptor agonists and uptake inhibitors were administered [35]. 

In a study by Umukoro et al. [42], MJ (1, 5, 10 mg/kg, intraperitoneally [i.p.]) had a dose-dependent decrease in aggressive behaviors in resident-intruder and isolation-evoked paradigms (both measures offensive aggression) in mice. Although MJ has an anti-aggressive activity, it, however, does not impair the defense mechanism of the animals. These findings suggest the therapeutic usefulness of MJ as an anti-aggressive agent. Its ability to maintain the defense mechanism in animals suggests that it could be a better therapeutic approach to aggressive behaviors than antipsychotics and high doses of benzodiazepines which tends to impair the defensive mechanisms of organisms [43]. 

Of all the neurochemicals associated with aggressive behaviors, reduced 5-HT has been recurrently linked with aggression by numerous authors [43,44]. This hypothesis was further proven using 5-HT1 knockout rodents [40-46] (Table 1).

Memory/Cognitive Enhancement 

MJ is used extensively in aromatherapy as a therapeutic agent for memory dysfunction [9]. In a study conducted by Umukoro et al. [22], intraperitoneal injection of MJ (25, 50, and 100 mg/kg) improved memory performance in mice exposed to UCMS. MJ was further shown to reverse UCMS-induced neurodegeneration in the sub-granular zone of the dentate gyrus and the pyramidal layer of the CA3 [22]. These learning and memory-associated regions of the brain have been reported to exhibit loss of dendritic spines [47] and a reduced number of synapses [48] following UCMS. The results of the study established that UCMS produced the death of neuronal cells in the pyramidal layer of the CA3 and the sub-granular zone of the dentate gyrus of the hippocampus, the regions of the brain that plays vital roles in learning and memory [22].

Thus, a decrease in hippocampal density may lead to a loss of memory function [49]. Previous clinical studies have linked reduced hippocampal volume to memory and cognitive impairment in patients with Alzheimer’s disease (AD) [49,50]. Thus, oxidative stress-mediated hippocampal neuronal degeneration highlights memory impairment due to chronic stress. However, there are suggestions that compounds with neuroprotective properties may be of benefit in chronic stress-induced cognitive deficits and other neuropsychiatric disorders [51,52]. In another study, Eduviere et al. [19] used the passive avoidance paradigm to evaluate the influence of MJ on rat memory. This model uses aversive stimuli associated with fear as a condition for learning and memory acquisition [53,54]. 

This model assesses both the role of the hippocampus in memory [55] and the amygdala in fear-conditioned learning and memory [56]. It tests the ability of rodents to suppress motor activities to avoid an aversive event, which is dependent on the capability of the organisms to recall unpleasant experiences [19]. The anti-amnesic activity of MJ was demonstrated using a passive avoidance task. MJ increased the latency period indicating an increase in the ability to retain and retrieve a memory. This test also demonstrated the mitigating effect of MJ pre-treatment on scopolamine-induced memory deficit. The test also demonstrates the attenuating effect of MJ on oligosaccharide-induced amnesia. 

These findings further support the hypothesis that MJ has a positive effect on the retention and retrieval of memory and that it plays a vital role in fear-conditioned memory. In different behavioral studies conducted by Umukoro and Eduviere [21] and Eduviere et al. [20] using the Y-maze paradigm, MJ attenuated memory deficits induced by lipopolysaccharide by increasing the alternation behavior of mice. The Y-maze is used to access spatial working memory, which is usually impaired in patients with AD. Therefore, heightened spatial working memory following MJ pretreatment indicates the anti-amnesic and memory-enhancing activity of MJ. Eduviere et al. [20] also used the object recognition test to assess the effect of MJ on the recognition memory of mice. The results showed that MJ significantly improved memory and attenuated scopolamine-induced memory impairment [20]. UCMS-induced memory dysfunctions were also attenuated by MJ via other mechanisms including Nrf2 expressions, and antioxidant and monoaminergic systems [57].

Antipsychotic 

Psychosis is a form of mental illness characterized by abnormal behaviors with little or no touch with reality [58]. It is characterized by multiple symptoms affecting thoughts, emotions, perception, and volition. It is a severe form of mental illness affecting the quality of life of the affected individuals [17]. Although pharmacological interventions have been the backbone of the treatment of the disease, the use of antipsychotic drugs has certain limitations. These include incidences of poor adherence, limited responses, and other incapacitating outcomes [59]. More notably, these drugs have failed to alter the course of the disease but are known to only provide symptomatic relief [17]. 

Likewise, the associated negative symptoms and memory deficits are not relieved by the antipsychotics [60-62]. Thus, the need to search for new drugs, especially agents with potential memory-enhancing effects as alternative treatments for psychotic disorders. Anna and colleagues [17] adapted the bromocriptine-induced and ketamine-induced stereotypes as models to screen for the antipsychotic-like effect of MJ. It was reported that MJ demonstrated reduced stereotyped behaviors such as persistent sniffing, chewing, intense licking, and head movements in mice, suggesting the antipsychotic-like property of MJ [17] (Table 1).

Anti-stress 

Increasing the prevalence of physical, biological, or psychological stressors lead to an increase in stress and subsequently a rise in dyshomeostasis [63,64]. Organisms normally respond to acute stress by adapting to the changes in their environment. However, prolonged stress leads to illness or cell damage. Prolonged stress has been implicated in a variety of diseases such as hypertension, immune dysfunction, cancer, and several neurodegenerative disorders [23,64]. Adaptogens are a classified group of substances with the ability to improve the mental and physical performances of organisms during exposure to stressful stimuli [65]. Numerous studies have employed behavioral, and biochemical techniques to demonstrate the anti-stress property of MJ [22,23]. 

MJ decreased the immobility time in FST and increased the latency to convulsion in the hypoxia test in mice exposed to acute stress [23]. MJ was shown to reduce the level of corticosterone secretion in stressed mice indicating its adaptogenic-like property. Corticosterone induces brain damage by increasing the intracellular level of oxidative stress. Chronic stress is known to trigger corticosterone release via the hypothalamic-pituitary-adrenal axis. This finding is further backed up by an increase in the adrenal gland and liver size which was noticed in UCMS-induced rats. Increased corticosterone levels can cause further damage via oxidative stress [50,66] and neuroinflammation [67]. 

MJ also decreased and increased the levels of malondialdehyde (MDA) and glutathione (GSH) which were originally increased and reduced respectively in the brains of mice exposed to UCMS. MJ subsequently attenuated the increased oxidative level induced by UCMS [18,22,57]. MJ has also been shown to possess anti-fatigue properties via its effect on the enzymes of the purinergic system [68].

To be continued......

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Oritoke Modupe Aluko1,2,3, Joy Dubem Iroegbu2 , Omamuyovwi Meashack Ijomone2,4, Solomon Umukoro3 

1 Department of Physiology, 

2 The Neuro-Lab, School of Health and Health Technology, Federal University of Technology, Akure, 

3 Department of Pharmacology and Therapeutics, University of Ibadan, Ibadan, 

4 Department of Human Anatomy, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria