Methyl Jasmonate: Behavioral And Molecular Implications in Neurological DisordersⅡ
Mar 28, 2023
MECHANISM OF MJ MODULATORY ACTIVITIES
Antioxidant
Oxidative stress has been implicated as a mechanism of cell damage and by extension, neuronal cell death. Oxidative stress occurs when there is a higher level of reactive oxygen species compared to antioxidants in the body. Various environmental stressors trigger the production of free radicals, which initiate a series of events leading to neurodegeneration [69,70]. Also, the inflammatory mediators released by injured neural cells additionally augment the production of free radicals resulting in neuronal cell death [69]. MJ amongst other adaptogens exhibits antioxidant properties (Fig. 2). This was seen in studies where MJ decreased and increased the levels of MDA and GSH which were originally increased and reduced respectively in the brains of UCMS-treated mice [20,22,57,71].
Click to cistanche tubulosa powder for AD&PD
In another study by Shanmugarajan [72], MJ significantly increased the activity of superoxide dismutase, glutathione-S-transferase, glutathione reductase, GSH Peroxidase, and catalase compared to the lipopolysaccharide-induced group, which further confirmed its antioxidant activity.
Inflammatory Biomarkers
Injured tissues undergo inflammatory responses to limit the level of damage and enhance healing [73]. Inflammation is mostly the underlying cause of pain. And also manifest in other forms such as redness, warmth, swelling, and loss of functions [74]. Anti-inflammatory drugs are designed to inhibit the action of cyclooxygenase enzymes (COX-1 and COX-2). These enzymes are responsible for the formation of prostaglandins, which are potent mediators of inflammation [75]. Chronic stress has also been linked to an increase in the release of pro-inflammatory cytokines, neuroinflammation, and subsequently depressive-like behaviors [66].
These inflammatory markers have been linked to the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease [76,77]. Interleukin-1 (IL-1) for example, is a well-known powerful pro-inflammatory cytokine with pleiotropic functional and behavioral functions [78,79]. IL-1 activates microglia and increases blood-brain barrier permeability, which promotes leukocyte permeation and upregulation of other pro-inflammatory molecules such as prostaglandin E2 (PGE2) and TNF- [78,79]. Clinical studies have linked elevated brain levels of inflammatory biomarkers in AD patients [78,80]. Also, a causative connection between IL-1 brain levels and memory deficits has been well reported in numerous literature [80,81].
Due to the structural similarity between MJ and anti-inflammatory prostaglandins, investigations are being carried out to ascertain its therapeutic potential for inflammatory disorders [5]. Lee et al. [82] and Dang et al. [4] investigated the anti-inflammatory potential of MJ in cultured cells. The inhibition of the NF-B signaling pathway led to the confirmation of the anti-inflammatory potential of MJ [82]. A similar pathway was observed in plants resulting from an increased level of jasmonate secretion following infections or injuries [1]. Umukoro and Eduviere [21] further examined the effect of MJ on inflammatory biomarkers in mice brains following lipopolysaccharide injection. In that study, MJ reduced the level of PGE2, inflammatory cytokines (TNF- and IL-1), COX2, iNOS, and NF-B. These findings further suggested the anti-neuroinflammatory activity of MJ. MJ (5−20 mg/kg, i.p.) reduced the increased level of TNF- in the brains of mice subjected to UCMS. MJ was also suggested to mitigate UCMS-induced anti-depressive behaviors via its inhibiting of oxidative stress and neuroinflammation [18]. Previous studies have also demonstrated the capability of MJ to silence genes involved in the synthesis of proinflammatory cytokines [4,83].
Neurotransmitter Regulation
Neurotransmitters are vital biochemical molecules that regulate behavioral and physiological functions in the CNS and PNS. Consequently, the study of neurotransmitters in biological samples has immense clinical and pharmaceutical importance [84]. MJ, an adaptogen, has been shown to regulate the synthesis and action of various neurotransmitters (Fig. 2). It enhances both serotonergic and noradrenergic transmissions [37]. It acts as a 5-HT1 receptor agonist, thereby enhancing serotonergic neurotransmission [42]. Studies incriminating noradrenaline and serotonin in the pathogenesis of depression are detailed in both preclinical and clinical pieces of literature [2,33,34,36,85].
Various agents such as MJ with antidepressant activity in rodents increase the extracellular availability of amines in the brain [37,86]. Although the exact mechanism of action of MJ needs to be explored before coming to any conclusions on its mechanism of action, preliminary investigations suggest that its antidepressant-like effect may involve serotonergic and noradrenergic mechanisms [37]. Additionally, MJ significantly reduces acetylcholinesterase activity in mice brains increasing brain-level acetylcholine. Acetylcholine is an essential neurotransmitter in the process of learning and memory [20,87,88]. There is also evidence of modulation of the monoaminergic system vis-à-vis adrenaline, dopamine, serotonin, and monoamine oxidase by MJ [57].
MJ also increases the immunoexpression of tyrosine hydroxylase in the midbrain and striatum of rotenone-induced rats [89]. Reduced tyrosine hydroxylase expression has been implicated in dopamine depletion [90,91]. These changes suggest the regulating activity of MJ on neurotransmitter synthesis and activity in the CNS.
Neuroregeneration
A key obstacle to neural repair is the weak regenerative ability of injured neurons, although the neonatal brain has more capacity for recovery than the adult brain. There are various reports on the role of some agents in promoting the regeneration of injured and degenerating neurons in the brain [92]. In a study by Umukoro et al. [22], MJ reduced the extent of neuronal damage in the pyramidal layer of the CA3 and the sub-granular layer of the dentate gyrus of mice subjected to UCMS [22]. They also quantified the neuronal cell population and reported increased neuronal density in the pyramidal layer of the CA3 and the sub-granular layer of the dentate gyrus in UCM-stressed mice following treatment with MJ [22]. Similar results were seen in a study by Eduviere et al.
[93] where MJ improved neuronal structure and density in the prefrontal cortex and CA1 of mice treated with lipopolysaccharide [93]. In another study, MJ reduced cytoarchitectural alterations and loss of neurons in the striatum of rotenone-treated rats [89]. MJ also significantly reversed structural alterations of the dendritic spine and improved dendritic density in rotenone-treated rats [89]. Additionally, it also reduced the loss of dopaminergic neurons in the midbrain of rotenone rats [89].
THERAPEUTIC POTENTIAL OF MJ IN NEURODEGENERATIVE DISEASES
Alzheimer’s Disease
Progressive memory loss is a major feature of Alzheimer’s disease, a neurodegenerative disorder. Its prevalence increases with age [94]. Its pathohistological hallmark includes neurodegeneration of brain regions associated with learning and memory like the hippocampus [94]. It is also associated with the loss of cells involved in the cholinergic pathway. Brain cells are highly susceptible to the damaging effect of reactive oxidative species (ROS) due to their elevated rate of utilizing oxygen and reduced antioxidant defense systems [20]. ROS initiates lipid peroxidation, which triggers neuronal degeneration, especially in the cholinergic system, and subsequently Alzheimer’s disease [20]. The role of oxidative stress in AD is confirmed by increased levels of MDA in post-mortem brains [95-97].
The potential of MJ as a therapeutic agent for the treatment of Alzheimer’s disease has been explored by numerous studies. MJ attenuated memory deficits induced by lipopolysaccharide by increasing the alternation behavior of mice subjected to the Y-maze test [21]. The Y-maze is used to access spatial working memory, which is usually impaired in AD. Therefore, enhanced spatial working memory following MJ treatment indicates its anti-amnesic and memory-enhancing activity. The histomorphological study by Umukoro et al. [22] demonstrated the ameliorative effect of MJ on UCMS-induced neuronal damage in the pyramidal and sub-granular regions of CA3 and DG respectively mice [22]. Neuronal damage in the hippocampus has been frequently linked to AD. MJ also attenuates the depleting population of hippocampal neurons in UCMS-subjected mice, further proving its neuroprotective effect. Since several neurochemical studies have been linked to neuroinflammation with AD pathogenesis [76,77].
Umukoro and Eduviere [21] accessed the therapeutic potential of MJ for AD by examining various neuroinflammatory biomarkers in lipopolysaccharide-treated mice. Their results showed a reduction in the level of PGE2, inflammatory cytokines (TNF- and IL-1), COX2, iNOS, and NF-B following MJ treatment. Inhibiting factors involved in the inflammatory process could be a useful therapeutic approach for this disorder [21]. Thus, it is safe to infer that the ability of MJ to overturn IL-1, PGE2, and TNF- levels suggests an important role in enhancing memory. Also, MJ suppressed the expression of A1−42 in the brain of mice treated with lipopolysaccharide, which suggests memory-enhancing properties. An increased level of A1−42 induces neuronal death, characterizing the pathological hallmark of AD [98,99].
Additionally, excessive accumulation of A in the brain further exacerbates oxidative stress and increases the inflammatory responses in progress, thus spreading neuroinflammation that results in progressive neurodegeneration and loss of cognitive functions in lipopolysaccharide-treated animals [77,98-100]. The attenuating effect of MJ on the level of A signifies its anti-amyloid genesis-like effect. It is also imperative to note that MJ is generally safe for use in humans, as it forms a major component of our diets like fruits and vegetables, thereby making it a promising therapeutic agent for AD [5].
Parkinson’s Disease
Parkinson’s disease (PD) is the second most popular neurodegenerative disease and is generally believed to primarily affect the dopaminergic neurons of the substantia nigra [101,102]. The pathological progression of PD is frequently believed to be a simple process that includes selective degeneration of the nigrostriatal pathway and a concurrent depletion in striatal dopamine [103]. This model has directed the development of the present therapies for PD and the investigations for new ones. Most of these focus on alleviating motor symptoms rather than modifying the disease [103]. The recognition of several non-motor symptoms of PD related to the degeneration of non-dopaminergic transmitter systems [104] has made these therapies less efficient.
These non-motor symptoms include olfactory dysfunction, sleep abnormalities, gastrointestinal dysfunction, anxiety, depression, and pain [105]. This, together with the fact that medications like levodopa lose efficiency and cause dyskinesias and behavioral anomalies in many patients, calls for the development of an efficient therapy that targets both the motor and non-motor pathways. Although there are numerous studies on the ameliorative potential of MJ on various non-motor symptoms associated with PD, it is however not certain if these signify a therapeutic effect of MJ against Parkinson’s disease. MJ attenuated the anxiety-like effect of UCMS in mice [22]. This is consistent with the result seen in a study by [18] where MJ (5−20 mg/kg, i.p.) improved spontaneous muscle activities which were initially decreased by UCMS in mice.
MJ reduced the immobility period in FST and TST [37]. The effect of MJ on motor symptoms was studied by Alabi et al. [89]. It reversed rotenone-induced deficits in locomotor activity and rearing behavior in rats. It significantly inhibited rotenone-induced dopamine reduction in the striatum, midbrain, and prefrontal cortex and increases the expression of tyrosine hydroxylase and dopamine in the striatum and the substantia nigra of rotenone-induced rats [89]. With the loss of dopaminergic neurons, the local supply of dopamine has been associated with motor deficits [106]. MJ also improves histomorphology by preventing and reverting neuronal damage in the SN and striatum of rotenone-induced rats. It preserved the dendritic network in the substantia nigra and striatum of rotenone-induced rats [89].
CONCLUDING REMARKS
The pathogenesis of many neurologic disorders and neurodegenerative diseases have causative associations with oxidative stress, inflammation, and neurotransmitter dyshomeostasis. These disorders exhibit symptoms such as anxiety, depression, aggression, psychosis, and memory impairment. Recent evidence highlighting the therapeutic potential of MJ in managing these symptoms and by extension, neurological disorders are reviewed. Reports from different studies reported MJ to possess the ability to act as an antioxidant, anti-inflammatory, anti-neurogenerative, and neurotransmitter-regulating agent. Its neuroprotective and anti-neurodegenerative properties in the rodents’ brains were also implicated in Alzheimer’s and Parkinson’s disease. Although various studies are highlighting the neuroprotective property of MJ, none has examined the exact mechanism of MJ. Therefore, further understanding of the mechanism of MJ acts will give better insight into modeling MJ as a targeted therapy for managing the diseases of the brain.
why does cistanche have neuroprotection effective
Cistanche is a natural herb that has been traditionally used in Chinese medicine to treat various health conditions, including neurological disorders. Studies have shown that cistanche contains certain bioactive compounds such as echinacoside and acteoside that have potent neuroprotective properties. These compounds have been found to protect the brain cells from oxidative stress and inflammation, which are the main causes of neurological damage and degeneration. Additionally, cistanche has been shown to improve blood circulation and enhance cognitive function, which further contributes to its neuroprotective effects. Overall, cistanche can be an effective natural remedy for promoting and maintaining brain health.
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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
