Neuroinflammation is a crucial part of the general pathology of several chronic and severe problems in the CNS [63]. The occurrence of neurologic diseases in people over 65 years is 1.8 and 2.6 for people aged 85 to 90 years, per 100 population [64]. The aggregation of damaging products caused by oxidative stress, such as glycated products, oxidized proteins, and lipid peroxidation, results in the destruction of neurons, which is more noticeable in brain disorders. Cerebrovascular diseases are characterized by vascular lesions that cause cognitive decline and dementia in old age [65].

Signaling molecules generated throughout the process of neuroinflammation meditate a number of pro-apoptotic pathways. In operating microglial cells, a transcription factor named NF-$\kappa$B induces and controls the expression of many vital components in inflammatory and immune feedback systems in the CNS and neurodegenerative disorders [65].

Kim et al. [66] found that protocatechuic acid (PA), an active phenolic compound of M. charantia, reduced the increased levels of NF-$\kappa$B, cyclooxygenase-2 (COX-2), and iNOS mRNA due to H${}_2$O${}_2$-induced oxidative stress. In addition, PA attenuated the production of interleukin (IL)-6 and reduced nitric oxide (NO) induced by endotoxin lipopolysaccharide (LPS) and interferon-gamma (IFN-$\gamma$) together. Furthermore, it reduced mRNA expression of iNOS and COX-2 induced by LPS and IFN-$\gamma$ [22].

M. charantia supplementation significantly reduced high-fat diet-induced brain oxidative stress in C57BL/6 mice, reducing blood–brain barrier (BBB) leakage, neuroinflammatory cytokines, NF-$\kappa$B1 expression, glial cell activation, and oxidative stress, while improving systemic inflammation [67].

Obesity increases the development of T-helper (Th) 17 cell genealogy, leading to inflammation [68]. IFN-$\gamma$, IL-17, and IL-22 are major cytokines liberated from Th1 and Th17 CD4+ cells. M. charantia decreases inflammation by reducing the liberation of plasma pro-inflammatory cytokines, IFN-$\gamma$, and IL-17 with tumor necrosis factor-alpha (TNF-$\alpha$), exotoxin-2, lymphotactin, and IL-1$\beta$ in mice fed with blue mussels (BM). Furthermore, M. charantia adjusted the Th2 cytokines IL-5, IL-10, and IL-13 to preserve obesity-associated inflammation [69]. However, in another study, the results were different, and Th2 cytokines such as IL-4 were shown to aggravate weight gain and high fat diet (HFD)-related hypothalamic inflammation [70]. In some studies, M. charantia adjusted neuroinflammatory and peripheral reciprocation by regulating the BBB [71, 72, 73, 74, 75]. Increased expression of IL-22 in the brains of HFD-fed mice may indicate glial cell activation, and feeding HFD to Sprague-Dawley rats reduced Sirtuin 1 (SIRT1) levels in the cerebral cortex and hippocampus, promoting oxidative stress. The observed 25% decrease of SIRT1 protein in the brains of HFD rats is lower than the 81% decrease reported by Wu et al. [75] in the cerebral cortex and hippocampus of HFD-fed mice. The levels of SIRT1 were different in the studies by Wu et al. [75] and others.

Horax et al. [76] reported that M. charantia contains various flavonoids, bitter triterpene aglycones, non-bitter cucurbitane, and glycosides that transmit antioxidants. Horax et al. [76] also showed that catechin is a major polyphenol in the seeds of BM and pericarp.

Deng et al. [77] used the chronic social defeat stress (CSDS) mouse model to assess the efficacy of Momordica charantia polysaccharide (MCP). MCP prohibits depressive-like behaviors brought on by CSDS. Moreover, MCP diminishes the amount of pro-inflammatory cytokines and restrains The c-Jun-NH(2)-terminal kinase (JNK3) and c-Jun production in the hippocampus. Furthermore, MCP protects against depressive-like behaviors in mice. Consequently, the protective efficacy of MCP in CSDS mice against depressive-like behaviors could be because of reduced neuroinflammation and down-regulation of the JNK3/PI3K/Akt pathway in the hippocampus [78].

In 2020, Kung et al. [78] studied the effects of wild bitter melon (WBM) on mouse models with spinal cord injuries (SCI), which induced secondary neuroinflammation. The investigators also used astrocyte-like cells stimulated by LPS for in vitro studies of astrocyte inflammation. They found that WBM reduces spinal cord injury. Furthermore, WBM, which contains alpha-eleostearic acid ($\alpha$-ESA), increases the viability and survival ability of astrocyte-like cells.

Mitochondrial malfunction and inflammation can lead to irreparable neuronal deficits. Chitosan/gelatin/sodium hyaluronate (CGSH) iron-sulfur domain 2 is a protein located on the outer membrane of mitochondria and is involved in maintaining the integrity of mitochondria and inhibiting apoptosis [79, 80]. Furthermore, CGSH iron-sulfur domain 2 reduces inflammatory responses caused by CNS injuries. Aging downregulates the expression of CGSH iron-sulfur domain 2, which aggravates mitochondrial malfunction and increases inflammatory responses [81, 82]. Spinal cord injury-induced downregulation of IL-4 is reduced by WBM because losing IL-4 increases microglial polarization from M2 to M1 [83]. WBM can increase the volume of M2 microglia, which are anti-inflammatory. The anti-inflammatory effects of WBM are therefore facilitated through the increase of CGSH iron-sulfur domain 2 in mice with spinal cord injuries and astrocyte-like cells stimulated with LPS. In addition, its protective effects in mice are shown by the deactivation of astrocytes and the downregulation of NF-$\kappa$B [83].

There have been reports of headaches following the consumption of M. Charantia seeds; however, there is no information regarding amyotrophic lateral sclerosis and headache severity or duration, or effectiveness as a treatment [84].

Macrophages are part of the first line of defense against injury, mediating the innate non-specific immune response via inflammation, and playing an important role not only in host defense but also in tissue homeostasis, repair, and pathology development, including MS. RAW 264.7 mouse derived macrophages have been widely used as an in vitro model to study the modulatory effects of various compounds using LPS for activation. It has been observed that treatment with Bitter Gourd (BG)-4 peptide extracted from M. Charantia has anti-inflammatory effects. In the investigation conducted by Nieto-Veloza et al. [84], BG-4 doses up to 375 g/mL had no effect on macrophage viability. It is known that LPS can activate NF-$\kappa$B, which acts as a master regulator of the inflammatory response by promoting the release of signaling and effector molecules such as pro-inflammatory cytokines (IL-6, TNF-$\alpha$, IL-1$\beta$) and NO that act as mediators of inflammation during the host immune response. MS and other inflammatory problems can be caused by the destruction of normal and healthy tissue caused by a continuous inflammatory condition; therefore, reducing the quantity of these pro-inflammatory produced molecules can lead to the management and treatment of these diseases. BG-4 dose-dependently inhibits NO and IL-6 production in LPS-activated RAW 264.7 macrophages. Moreover, BG-4 reduces the expression of iNOS and COX-2 [85].

AD is among the most prevalent of neurological diseases. Oxidative stress and the abnormal increases in A$\beta$ are the most common causes of AD. Dementia is seen in patients with AD and occurs when A$\beta$ accumulates in brain tissue, including in the cerebral cortex. Common treatments are cholinesterase inhibitors and receptor antagonists, but they cannot efficiently treat patients [23, 86, 87].

According to an in vivo study by Sin et al. [23], 100 and 200 mg/kg/day of butanol (BuOH) fraction derived from M. charantia can improve memory and learning in the A$\beta$ (25-26)-induced AD mouse model. Furthermore, oral prescription decreased HNO${}_3$ and lipid peroxidation in the brain compared with the control group [24]. Combination therapy including M. charantia and lithium chloride in ovariectomized AD female mice reduced gliosis, neuronal loss, and tau hyperphosphorylation, suggesting the potential for AD treatment [88].

In an in-silico study [89], luteolin, extracted from M. charantia, increased ACh in neuronal cells by attaching to acetylcholinesterase and butyrylcholinesterase. The authors suggested luteolin as a multi-target molecule against AD. Luteolin can therefore effectively act as a multi-target molecule against AD. The summarized effects of M. charantia on age-related neurological disorders is shown in Figs. 4,5.

Fig. 4.

Summary of Momordica charantia’s effects including anti-oxidant, anti-cancer, anti-glioma, anti-Alzheimer’s disease, and anti-Parkinson’s disease. Arrows indicate mechanism of actions of M. charantia. Keap1 is the factor accommodating Nrf2. MTPT, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NF-$\kappa$B, nuclear factor kappa-light-chain-enhancer of activated B cells; TLR4, toll-like receptor 4; MAP2, microtubule-associated protein 2; BACE-1, beta-site amyloid precursor protein cleaving enzyme 1; PSD95, postsynaptic density protein 95; Nrf2, nuclear factor erythroid 2-related factor 2; CAT, chloramphenicol acetyltransferase; SOD, superoxide dismutase; MDA, malondialdehyde; MyD88, myeloid differentiation primary response 88; P, phosphorylation; CAT, chloramphenicol acetyltransferase; Tau, tubulin associated unit.

Fig. 5.

Summary of pathways: Momordica charantia acts in Gliomas, Glioblastomas, neurotoxicity, and Alzheimer’s disease, and on neuroinflammation, serotonin, and acetylcholine. Glutamate-activated AMPA and NMDA receptors mediate A$\beta$ accumulation. ROS, reactive oxygen species; ACh, acetylcholine; NF-$\kappa$B, nuclear factor kappa-light-chain-enhancer of activated B cells; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2; AMPA, $\alpha$-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-D-aspartate; PI3K, phosphoinositide 3-kinases; Akt, protein kinase B; P, phosphorylation; A$\beta$, amyloid-beta.

A study [90] reviewed the therapeutic role of $\alpha$-ESA, an isomer of conjugated linolenic acids produced from wild bitter melon (Momordica charantia L. var. abbreviata Seringe), and curcumin in CNS illnesses. In addition, the authors highlighted the probable role of glia-mediated neuroinflammation, mitochondrial dysfunction, CDGSH iron-sulfur domain 2 (CISD2) loss, and NF-$\kappa$B activation in CNS traumas and disorders. Their review enhances our understanding of the CNS pathology–CISD2–NF-$\kappa$B axis and clarifies the possible therapeutic role of these natural chemicals [90].

A study [90] investigated the neuroprotective benefits of sulforaphane (SFN) on cognitive illnesses such as AD, PD, Huntington’s disease, amyotrophic lateral sclerosis, MS, autistic spectrum disorder, and schizophrenia in a separate review. they described the anti-AD-like action of SFN and how it reduced levels of AD biomarkers, including A$\beta$, tau, inflammation, oxidative stress, and neurodegeneration in AD-like animal and cell models. In addition, the authors concentrated on the probable mechanisms behind the neuroprotective benefits of SFN. This review reveals that SFN has multiple neuroprotective effects on the pathophysiology of AD, highlighting the necessity to continue SFN research [90].

Yoshinori Okada and Mizue Okada [90] evaluated the protective effects of plant seeds against A$\beta$-induced neurotoxicity in hippocampal neurons. They examined the aqueous extracts of 15 plant grains for their ability to inhibit A$\beta$ (25-35)-induced cell death using hippocampal neurons. The aqueous juices showed antioxidant properties. Furthermore, intracellular cumulative ROS resulting from A$\beta$ declined when cells were cured with some of these extracts. Kale, bitter melon, red shiso, kaiware radish, and corn inhibited TNF-$\alpha$ in A$\beta$-stimulated neurons and, in all instances, Japanese honeywort displayed better cell survival. This study showed that some plant seed juices offer protection against A$\beta$-mediated death in cells.

Katsouri et al. [91] showed promising results regarding a lithium chloride (LiCl) compound, including increased cognition and short-term memory, as well as decreased amounts of oligomer, tau protein phosphorylation, and BACE-1 expression, and improved expression of synaptic plasticity-related proteins. Other neuroprotective results have been reported by synthesizing LiCl with L-dopa or other histone deacetylase inhibitors [67, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101]. Many studies showed that synthesizing therapies with multifold drugs has better therapeutic potential for AD [102, 103, 104, 105].

Epilepsy is a common condition that affects the brain and causes frequent seizures. Seizures are bursts of electrical activity in the brain that temporarily affect how it works, causing many symptoms. Epilepsy can start at any age but usually it starts in childhood or in people over 60 years [106]. The drugs that are currently available to treat epilepsy might adversely affect human health. The herbal medicines that have been used in the past and traditional medicines have fewer side effects [107].

Soliman et al. [107] investigated the anticonvulsant potential of M. charantia in rats. Thirty minutes after treatment, ear electrodes were used to give rats a 150 mA shock. According to the reported results, M. charantia might have tremendous anticonvulsant effects against maximal electroshock-induced seizures and reduce the duration and delay the onset of seizures [108].

PD is the second most common neurodegenerative disease after AD [109, 110]. The cause of PD is not yet well understood, but genetic and environmental factors, including poisons, are proven to contribute to its development [111]. In PD, dopaminergic neurons in the substantia nigra compact area are lost, and Lewy bodies accumulate in the brain [112]. The active metabolite of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) is N-methyl 4-phenylpyridinium (MPP${}^{+}$). MPTP is a neurotoxin that specifically targets dopaminergic neurons and causes PD [113]. Evidence indicates that inflammatory damage and oxidative stress can accelerate the disease [25].

Natural ingredients such as polysaccharides in plants delay aging and protect the brain. Momordica charantia polysaccharides (MCPs) have been studied for their antioxidant, anti-inflammatory, anti-tumor, hypoglycemic, and anti-diabetic effects [19]. Little is known about their role in the regulation of neurogenesis [114]. However, MCPs reduce nerve damage after stroke by scavenging free radicals [42].

MCPs showed neuroprotective effects in MPTP- and MPP${}^{+}$-induced PD in mice. A study on mice reported that MCPs alleviated the exercise instability and loss of coordination caused by MPTP, inhibited the release of inflammatory factors and oxidative stress products in the brain, and, as a result, increased dopamine levels. Regarding cell function, MCPs inhibit apoptosis and oxidative stress induced by MPP${}^{+}$. The authors also observed that MCPs can protect against oxidative stress by inhibiting the transcription of Toll-like receptor 4 (TLR4)/Myeloid differentiation primary response 88 (MyD88)/NF-$\kappa$B [114]. The TLR4/MyD88/NF-$\kappa$B pathway is thought to play a vital role in the inflammatory process [115, 116]. Observing the changes in this signaling pathway showed that MCPs can affect the status of the TLR4/MyD88/NF-$\kappa$B pathway. There are various TLR4 inhibitors, among which Resatorvid (TAK-242) is a bioavailable TLR4 inhibitor that inhibits extensive inflammation [117]. As a result of the combined use of MCPs and TAK-242 in the PD condition, the investigators found that TAK-242 could reverse the protective effects of MCPs, therefore proving the effectiveness of MCPs on the TLR4/MyD88/NF-$\kappa$B signaling pathway [114].

Increasing the average life expectancy is one of the most significant achievements of the past century [118, 119]. However, a healthy lifestyle and life expectancy free of disease have not increased as much [118, 120]. In addition to disability and reduced physical strength, aging is a risk factor for chronic diseases and cancer, and it has become a pervasive challenge [118, 121, 122]. Research to identify the causes of these destructive changes in the body that occur with the aging process and find a solution to reduce these changes will therefore help to increase quality of life and personal productivity. Cancer and tumors are a group of age-related diseases that we are facing more often due to increases in the average age of society. Prolonged exposure to endogenous and exogenous factors contributing to oxidative stress can eventually lead to gene mutations and inflammatory processes [123]. Antioxidant therapy is therefore accepted as one of the main methods to limit cell damage caused by oxidative stress [124, 125]. Many studies have been conducted to find effective natural and artificial antioxidants for fighting excess free radicals. Currently, people older than 65 years comprise around 60% of all patients with malignant tumors, and they make up 69% of whole cancer deaths [126]. Based on etiology, some highlighted common causes of aging and cancers include oxidative damage and deoxyribonucleic acid (DNA) damage [127, 128, 129, 130], cellular senescence [131], and insulin/insulin-like growth factor-1 (IGF-1) signaling [132].

In a study by Manoharan et al. [132], the impacts of $\alpha$- and $\beta$-momorcharin (200-800 µM) on WERI-Rb-1, SK-MEL, 1321N1, COR-L23, and U87-MG cancer cells lines were compared with the normal and balanced L6 myocytes line. $\alpha$- and $\beta$-momorcharin decreased viability, increased cytochrome c release, and enhanced calcium concentration in treated cells. The authors reported 800 µM as the most effective concentration. Furthermore, other studies have suggested that $\alpha$- and $\beta$-momorcharin can trigger a receptor on the membrane surface of cancer cells or may infiltrate the cell by its osmotic effect [133, 134, 135]. This substance is also assumed to damage the cancer cells’ mitochondria, leading to apoptosis by improving the caspase-3 and caspase-9 processes, releasing cytochrome c and intracellular Ca${}^{2+}$ [136, 137]. In conclusion, M. charantia, which contains $\alpha$- and $\beta$-momorcharin, can effectively lead to cancer cell apoptosis and may be a suitable anti-cancer option.

M. charantia is a plant with medical effects, such as anti-inflammatory [138, 139, 140, 141, 142, 143, 144, 145] and anti-cancer effects, as well as anti-diabetic and antiviral activities [146, 147]. Its evaluation is therefore valuable for discovering its influential factors. Previous studies identified some of its beneficial components, including the ribosome-inactivating proteins $\alpha$- and $\beta$-momorcharin, cucurbitacin B, and momordin, and the chemical analog MAP30 protein [148, 149, 150, 151]. A few study found two new triterpenoids, D [146] and E [147] charantagenin. A novel sterol, 7-oxostigmasta-5,25-diene-3-O-$\beta$-D-glucopyranoside, was isolated [152] in addition to eight known compositions [153, 154, 155, 156, 157, 158, 159]. The results confirmed that this novel composition was more abundant than the others and that another (guaglycoside D) contained an O-Methyl (OMe) substituent in the side chain, which was effective against cancer cells and had impressive cytotoxic effects. In addition, they had lower IC${}_{50}$ values compared with other components. It is worth noting that IC${}_{50}$ is applied to measure drug efficacy, as it corresponds to the potency of the drug. These findings suggest the level of OMe may be associated with the cytotoxic activity of cucurbitane-type triterpenoids. The cucurbitane-type triterpenes, especially from M. charantia, therefore probably have potential anti-cancer effects similar to chemotherapy.

Glioblastoma multiforme (GBM), also referred to as a grade four astrocytoma, is a fast-growing and aggressive brain tumor. It invades the nearby brain tissue but does not spread to distant organs. Gliomas are tumors that have a peak incidence in middle-aged humans [160]. Gliomas account for over half of all intracranial tumors [161]. The average annual age-adjusted incidence rate of glioma is estimated at 6 per 100,000 population [162]. These tumors are the most common primary tumors in the brain, originating from different glial cells, including oligodendrocytes, astrocytes, and ependymal cells [163]. Standard of care includes surgery, radiation therapy, and chemotherapy. However, due to the exceedingly invasive capability of glioblastoma cells, tumors develop over time and integrate into surrounding brain tissue [164].

Wang et al. [161] found that M. charantia impedes viability and reduces the multiplication of U251 glioma cells, repressing their influx, which has an anti-glioma effect. However, it had no considerable efficacy in the apoptosis of these cells. Moreover, M. charantia-derived extracellular vesicle-like nanovesicles exert anti-glioma effects by adjusting the PI3K/Akt signaling route [165]. In an in vitro study the effects of the anti-tumor activity of M. charantia (MAP30) on proliferation, migration, and invasion of the U87 and U251 cell lines were assessed [166, 167]. MAP30 inhibited U87 and U251 cell viability in a dose‑ and time‑dependent manner and decreased colony formation of these cell lines. It also induced apoptosis and S-phase cell cycle arrest by breaking the bonds of the adenine‑ribose glycoside. The invading proportions of the cells treated with MAP30 were significantly lower than their control counterparts. Western blot analysis indicated decreased leucine rich repeat containing G protein-coupled receptor 5 (LGR5) expression and increased Smac (activator of intrinsic apoptosis) expression in cells treated with MAP30. The Wnt/$\beta$‑catenin and LGR5 signaling pathways play a vital role in the tumorigenesis of gliomas [26, 168, 169, 170, 171]. Manoharan [26] investigated the performance of $\alpha$- and $\beta$- momorcharin obtained from M. charantia by combining cyclophosphamide with the cellular mechanisms. Compared with cyclophosphamide’s effect, the results showed significant decreases in cell viability for each cell line in the presence of active substances [172].

Furthermore, 800 µg of the crude water-soluble M. charantia extraction in combination with 250 µg of paclitaxel showed a significant decline in cell viability of five cell lines mentioned earlier [173]. Another study on the U87G Glioblastoma cell line showed that M. charantia extraction displays a cytotoxic and anti-proliferative role and might be helpful as a therapeutic agent against GBM [174]. According to these studies, M. charantia can be considered a plant with pharmacological and nutritional properties. Its compounds make this plant a potential anti-carcinogenic agent and therapeutic aid for the treatment of glioma.

Stroke is the second leading cause of disability and death worldwide, and has the most concerning and excessive burden in countries with revenue deficiency. The universal number of incidents was 13.7 million in 2016, and it is estimated that 87% of those were ischemic stroke [27]. Furthermore, stroke is one of the world’s most prevalent vascular ailments and remains the fifth leading cause of death in the United States [175]. Brain ischemia could be focal or multifocal and is caused by an abrupt cessation or diameter reduction of the artery supply of a region in the brain. The decreased brain blood supply leads to hemodynamic dysfunction, which contributes to damage to the brain tissue [28]. There are some uncommon causative agents of ischemia. Rarely, dissection of cervical blood vessels causes brain ischemia and may cause stroke in younger patients. Another rare cause of brain ischemia is vasospasm. An infection can also lead to stroke.

It should be noted that an increased stroke incidence has occurred with the COVID-19 pandemic [174]. Aging and related conditions, including diabetes, could be important factors in ischemia manifestation. Special attention must therefore be paid to ischemia as an age-related disorder.

The potential neuroprotective effect of the freeze-dried juice of fresh M. charantia in cerebral injury caused by ischemia-reperfusion was studied by Malik et al. [27] using cerebral infarct size, measuring thiobarbituric acid reactive substances (TBARS) and immediate memory and motor activity. Cerebral oxidative stress and damage with a shortfall in neurological functions were observed related to the dosage. The authors reported that the manifestations were extenuated by lyophilized M. charantia juice pre-treatment. M. charantia might therefore be an efficient option with neuroprotective activity in treating patients with stroke [27].