Pathophysiology and Therapeutic Perspectives of Oxidative Stress and Neurodegenerative Diseases: A Narrative Review

The pomegranate fruit, which originated in India but is today cultivated around the world, is rich in antioxidants. The primary polyphenol antioxidant of the pomegranate is punicalagin (PN) or 2,3-hexahydroxydiphenoyl-gallagyl-d-glucose. As a natural antioxidant, PN offers many health benefits and has an anti-inflammatory effect. The potential neuroprotective benefit of PN in the treatment of Parkinson’s disease has been described in the literature [69].

Traditional Persian medicine (Falij, Ra’shah, Nisyān, Khadir, Istirka) emphasizes the role of certain plants for preventing and treating neurological conditions. These botanicals use cellular and molecular mechanisms to slow or stop apoptosis, including anti-apoptotic agents (BCL-2) or by decreasing the expression and activity of pro-apoptotic proteins (BAX, caspase-3, and caspase-9). These traditional plants are thought to alleviate inflammation and reduce the production of pro-inflammatory cytokines (TNFα, various IL cytokines) while at the same time promoting antioxidation by enhanced production of superoxide dismutase and catalase. These traditional plants can modulate the transcription, transduction, and signaling of various inflammatory pathways (including ERK, p38, MAPK). By regulating these inflammatory cascades far upstream, they can help limit apoptosis and OS and, in this way, may help prevent or treat neurodegenerative conditions [70].

Vitamin D reduces OS, offers both neuroprotective and anti-inflammatory actions, and may exert preventive effects on neurodegenerative diseases [71].

When vitamin C (200 and 400 mg/kg body weight) was administered to rats who had colchicine-induced Alzheimer’s disease (cAD), the rats recovered some memory deficits, hippocampal neuroinflammation was reduced, and further neurodegeneration was prevented. The hippocampal neuroinflammation had had an adverse effect on the peripheral immune responses which was also recovered. However, when the rats with cAD were administered higher doses of vitamin C (600 mg/kg), memory impairments resulted along with hippocampal neuroinflammation, and neurodegeneration along with altered peripheral immune responses. These are all pro-oxidant, rather than antioxidant, effects [72].

Bakkenolide B is a natural substance obtained from the Petasites japonicus plant which has been shown to suppress both inflammatory and allergic responses. Treatment with bakkenolide B reduced production of microglia, IL-1β, IL-6, IL-12, and TNFα [73].

A review of scientific evidence about the Mediterranean diet and its emphasis on extra-virgin olive oil found this diet may decrease the risk for neurodegenerative diseases [74]. The health benefits of olive oil were presented in 2016 by Parkinson and Cicerale [75]. Their work came after an announcement that phenolic compounds such as oleocanthal or oleuropein found in olive oil might confer neuroprotection and possibly prevent Alzheimer’s disease [76, 77]. In fact, the Prevención con Dieta Mediterránea study (PREDIMED) found that the Mediterranean diet with extra-virgin olive oil and nuts was associated with improvements in cognition [78]. The Mediterranean diet may benefit patients at all stages of Alzheimer’s disease by slowing the rate of cognitive decline, delaying dementia, and reducing the risk of death [79]. Moreover, other benefits of extra-virgin olive oil include neuroprotective effects in the setting of depression, Parkinson’s disease, traumatic brain injury, and multiple sclerosis [80, 81].

Flavonoid is a collective term for a diverse group of phytonutrients found in most fruits and vegetables. Overall, flavonoids act as antioxidants and offer neuroprotection by fighting neurotoxins. Flavonoids can reduce Aβ production. Because flavonoids in general reduce or inhibit neuroinflammation, they tend to promote proper function of the cerebrovascular system and, in that way, may improve cognition [82].

Recently gaining in popularity, curcumin (found in the turmeric plant) has known anti-inflammatory, antioxidative, and antitumor properties. Widely used around the world as an herbal remedy, curcumin or turmeric is increasingly recommended by Western medicine as a pain reliever. It may also confer neuroprotection [83]. Turmeric is also used as a spice and is particularly popular in Indian cuisine.

Resveratrol (3,4′,5-trihydroxy-trans-stilbene) is a phytonutrient found naturally in about 70 plants, including the skin and seeds of grapes. In addition to the powerful antioxidant effect of resveratrol, its antitumor activity is currently being studied in cancer patients. Resveratrol has demonstrated neuroprotective properties in several in vivo and in vitro models because it inhibits glutathione depletion. Glutathione is an antioxidant produced by the CNS involved in numerous cellular processes. When glutathione is depleted, the neuronal system becomes vulnerable [84].

Aged garlic extract (AGE) is made when the garlic plant Allium sativum is marinated under ambient conditions in aqueous ethanol for four or more months. Through this process, much of the sharp taste and offensive odors of the garlic plant are eliminated and, more importantly, the antioxidative properties of the product are amplified. Neuroprotective benefits in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and cerebral ischemia have been observed with AGE [85]. AGE appears to act on the signaling pathways involved in OS and neuroinflammation, although this mechanism of action remains to be more fully elucidated [85]. Two components of AGE, S-allyl-l-cysteine and N(α)-(1-deoxy-d-fructos-1-yl)-l-arginine, seem to attenuate neuroinflammation in the microglia by modulating the nuclear factor erythroid 2-like (Nrf2)-mediated pathways as well as attenuating other forms of oxidative stress signaling [85].

NF-κB is a transcription factor involved in multiple physiological and pathological conditions. Among other things, NF-κB regulates DNA transcription, production of cytokines, and plays a role in cell survival. Thus, NF-κB is directly or indirectly involved in immunological responses, apoptosis, inflammatory processes, and carcinogenesis. The role of NF-κB and Nrf2 was investigated to better elucidate their contribution to OS and inflammation associated with neurodegenerative diseases. Botanical polyphenols have been shown to inhibit lipopolysaccharide (LPS)-induced nitric oxide responses and enhanced antioxidant responses modulated by Nrf2 [86]. Using an immortalized rat astrocyte (DI TNC1) cell line which expressed a luciferase reporter driven by the NF-κB or their Nrf2/antioxidant response element (ARE), investigators showed how these two pathways could be regulated by phytochemicals (such as quercetin, rutin, cyanidin, cyandini-3-O-glucoside) and botanical extracts from Withania somnifera (ashwagandha), Sutherlandia frutescens (sutherlandia), and Euterpe oleracea (açaí). All three of these botanical extracts inhibited LPS-induced NF-κB-reporter activity. For example, quercetin inhibited the LPS-induced NF-κB reporter activity on the one hand and induced reporter activity of Nrf2/ARE on the other hand. Cyanidin and glycoside had similar effects but only when used at much higher concentrations. Investigators stated that ashwagandha extract was more effective than sutherlandia and açaí extracts in promoting Nrf2 and HO-1 expression in DI TNC1 astrocytes, which illustrates how botanical polyphenols and extracts have different abilities in terms of downregulating LPS-induced NF-κB and upregulating NRF2/ARE [87].

Hericium erinaceus is a mushroom that was found to confer certain neuroprotective properties in animal studies. Rats administered the mushroom orally were found to have upregulated lipoxin A4 (LXA4) in various parts of their brains. LXA4 is thought to help reduce inflammation by halting the inflammatory processes and increase redox-sensitive proteins in response to cellular stress, such as heat shock proteins, HO-1, and thioredoxin [88]. Heat shock proteins have been implicated as a potential pathway for the prevention of protein misfolding, which has been associated with certain types of irreversible neuronal damage. It has been suggested that agents that can activate LXA4 signaling would be able to modulate the vitagene proteins that respond to stress cues; in that way, agents that activate LXA4 might be good targets for reducing the neuroinflammation and neurodegeneration associated with Alzheimer’s disease [88].

Peptides from the walnut have been studied for their hypothesized ability to protect against neurotoxicity. Mice were injected bilaterally in the hippocampus with amyloid-β peptide 25–35 to create an animal model of Alzheimer’s disease [89]. Mice were then treated orally with walnut peptides (200, 400, 800 mg/kg) or distilled water (placebo) for 5 weeks. The water maze and step-down avoidance tests were used to test the mice at 5 weeks for spatial learning and memory. Walnut peptides improved the cognitive abilities and memories of the animals compared to placebo. Furthermore, the two higher-dose walnut peptide groups (400 or 800 mg/kg) had restored levels of antioxidant enzymes and inflammatory mediators. This in vivo study suggests that walnut peptides might exert a neuroprotective effect in Alzheimer’s disease by reducing neuroinflammation and enhancing the endogenous antioxidant system [89].

One of the chemical components from Chinese celery (Apium graveolens L.), l-3-n-butylphthalide (l-NBP), has shown neuroprotective benefits in animal models of stroke and Alzheimer’s disease [90]. A synthetic version of this substance is an approved anti-ischemic agent available in China. In a preclinical study, C57BL/6 mice were administered systemic LPS that resulted in the release of pro-inflammatory cytokines and activated cerebral microglia. When these mice were treated with l-NBP, the production of pro-inflammatory cytokines such as TNFα, IL-1β, ΙL-6, and IL-10 was suppressed, and the morphological activation of microglia was decreased [91]. The phosphorylation level of the Janus kinase (JAK) mitogen-activated protein (MAP) pathways was also inhibited with the administration of l-NBP in these mice. HO-1, which helps to catalyze the degradation of heme and has anti-inflammatory and antioxidative effects, was also evaluated in this murine study and found that l-NBP was associated with an upregulation of HO-1 expression.

Highly regarded in traditional Chinese medicine, the tianma flower from the orchid family (Gastrodia elata Blume) has been used in Chinese folk medicine for centuries to treat a wide range of complaints ranging from headache to convulsions. Today it is known for its analgesic and sedative effects, and it shows promise in the treatment of neurological disorders. An extract from its rhizome has been observed to provide neuroprotective effects. In an animal model of brain injury, this extract helped brain cells to recover their function, likely by inhibition of both OS and the inflammatory response [92].

Chrysophanol is an anthraquinone well known in traditional Chinese and Korean medicine. It is widely distributed around the world in two main natural domains: Bacteria and Eukarya. It has a reputation for benefits in anticancer, hepatoprotection, neuroprotection, anti-ulcer, and antimicrobial applications. Its neuroprotective effects and its ability to reduce OS were evaluated in vitro with LPS-induced inflammatory responses in bovine BV2 cells. In this study, chrysophanol reduced the expression of iNOS and COX-2, and, in that way, nitric oxide and prostaglandin E₂ production were reduced [93]. Chrysophanol inhibited DNA oxidation and was also able to reduce cell damage in these BV2 cells caused by intracellular reactive oxygen species. To measure the overall antioxidant effect, the expression levels of various antioxidative enzymes, such as superoxide dismutase, and glutathione were calculated. Chrysophanol was shown to exhibit potential anti-inflammatory and antioxidative effects in the microglia, making it a potentially valuable therapeutic product in the treatment of neurodegenerative diseases [93].

Seafood is frequently recommended by dieticians for its health benefits, most of which come from omega-3 and omega-6 polyunsaturated fatty acids (PUFAs), n-3/n-6 PUFAs, and antioxidants. The ratio of omega-3 to omega-6 PUFAs is more important to health than their individual quantity. The intake of the proper ratio of omega-3 to omega-6 PUFAs can allow for effective anti-inflammatory responses that may be able to prevent or delay neurological disorders. Early in vivo and clinical studies using the marine carotenoid astaxanthin found in salmon, shrimp, and lobster show that it can protect against neuronal damage caused by free radicals that can lead to neurodegenerative processes and cognitive deficits [94]. Nutraceutical products have been created with a balanced ratio of omega-3 and omega-6 PUFAs combined with astaxanthin as protection against neurodegeneration caused by OS in the CNS. Other antioxidants such as krill oil can be combined in such products.

Palmitoylethanolamide (PEA) is an endogenous lipid that was first brought to the attention of physicians when the anti-inflammatory effects of egg yolks were studied. (PEA occurs naturally in egg yolks.) PEA is available today as a “special food for medical purposes,” as registered by some pharmaceutical agencies. It down-modulates mast cell activation, allowing it to exert control over certain glial cell behaviors. PEA, an acylethanolamide found in diverse bodily tissues, including the nerve cells, can be synthesized by the body as needed. In fact, endogenous PEA levels vary regularly in the body, for example with stress, injury, or pain [95]. PEA is associated with reducing mast cells, down-modulating the pro-inflammatory mediators released by these mast cells, and suppressing microglial cell activation. These activities are thought to be the reason PEA is associated with anti-allodynic and anti-hyperalgesic effects. At the molecular level, PEA is a peroxisome proliferator-activated receptor alpha (PPARα) ligand with anti-inflammatory, analgesic, and neuroprotective properties [96]. Clinical trials using PEA in humans have shown promise. For example, PEA was effective in a preliminary trial of patients with failed back surgery syndrome [96] and in another study of patients with fibromyalgia [97] because of its anti-inflammatory properties. These neuroprotective and anti-neuroinflammatory properties make PEA an interesting substance to consider as a novel therapy for Alzheimer’s disease. Beggiato and colleagues found that astrocytes contribute to the neurotoxicity induced by amyloid-β42 (Aβ42); PEA could blunt the activation of Aβ42 and, in that way, induce astrocyte activation and improve neuronal cell survival in murine astrocyte–neuron co-cultures [98]. On the basis of the neuroprotective attributes exhibited in experimental models of neurodegenerative diseases, an ultra-micronized (um) form of PEA has been developed and investigated for the treatment of cognitive impairment [68]. In these studies, it was found that PEA may be a component of the homeostasis involved in the resolution of neuroinflammation. In an animal model of Parkinson’s disease, chronic PEA treatment was able to counteract behavioral impairments, motor dysfunction, loss of nigrostriatal neurons, astrocyte activation, altered iNOS expression, and proteins associated with the microtubules. In this Alzheimer’s disease model, when Aβ25–35 peptides were injected into the intracerebral ventricles of the murine brain, PEA treatment could ameliorate behavior impairments and reduce lipid peroxidation, iNOS, and caspase-3 activation [68]. In human patients with ALS, PEA improved their clinical conditions and delayed tracheotomy and death [68].

As a natural substance that acts like a neurotransmitter, melatonin plays a role in a variety of bodily functions. Produced endogenously and mainly but not exclusively by the pineal gland, melatonin has known benefits for treating sleep disorders, boosting natural immunity, and offering anti-aging benefits as well. An indolamide, melatonin is perhaps best studied for its regulation of circadian rhythms, but it may be involved in a host of other functions such as oxidation, apoptosis, and mitochondrial homeostasis. When inflammatory pathologies disrupt the last three processes, melatonin appears to offer some therapeutic benefits, particularly in patients with neurodegenerative diseases or bowel disease. Among the neurodegenerative conditions in which melatonin has been studied are Alzheimer’s disease, ALS, multiple sclerosis, and Huntington’s disease; melatonin may also be effective in treating patients with ulcerative colitis [99].

The combination of curcumin plus melatonin as an oral hybrid compound might be effective as a disease-modifying agent in the treatment of Alzheimer’s disease. In an in vivo study using a transgenic model of Alzheimer’s disease, Z-CM-I-1 administered at 50 mg/kg orally over 12 weeks decreased the accumulation of amyloid-β in the hippocampal and cortex regions of the brain and it further reduced inflammatory response and OS. In addition, with Z-CM-I-1 there was significant improvement of synaptic dysfunction (as shown by increased expression of synaptic marker proteins, PSD95, and synaptophysin which shows protective effects against synaptic degeneration). Z-CM-I-1 also increased the expression levels of complexes I, II, and IV of the mitochondrial electron transport chain in the brain tissue of mice [100].

TXNIP is produced endogenously and inhibits thioredoxin, a thiol-reducing and antioxidative system in the body. In the healthy individual, the role of TXNIP is to control the processes of stress and inflammation induced by redox and glucose. During cerebrovascular accident and brain disease, TXNIP is upregulated. Recent studies suggest that pharmacological inhibition or even genetic deletion of TXNIP can serve to protect the neurological system, possibly reducing the adverse effects of neurodegenerative disease or stroke [101].

In the early stages of Alzheimer’s disease, patients are known to experience synaptic pathologies and mitochondrial oxidative damage. For this reason, mitochondria-targeted molecules were conceived as therapeutic targets that might delay or prevent the advancement of Alzheimer’s disease. Mitochondria-targeted molecules are designed to deliver treatment directly to the mitochondria, reducing reactive oxygen species and mitochondrial dysfunction and, in that way, preventing or delaying neurodegeneration. Mitochondria-targeted molecules are cell-penetrating triphenyl phosphonium lipophilic cation-based derivatives of tetrapeptide molecules or choline esters of glutathione and N-acetyl-l-cysteine [102].

Receptors for advanced glycation end products (RAGE) are receptors expressed in numerous CNS and peripheral cells, including neurons, astrocytes, microglia, and others. These receptors bind to a select number of ligands, including non-enzymatically glycated proteins and certain lipids. The importance of RAGE is its critical role in the inflammatory process and the possible role it may play in neurodegeneration. H₂S inhibits dimer formation of RAGE and, in that way, impairs the stability of its membrane. By reducing the RAGE membrane, H₂S may protect cells against the adverse effects of inflammation [103, 104]. Its role in the treatment of various neurodegenerative diseases remains to be clarified.

Heat shock proteins (HSPs) took their name when a family of proteins was discovered which was created during heat shock. Although heat shock proteins retain their old name, it is now known that they are produced in response to any number of external and internal stressors including thermal stress, wound healing, tissue remodeling, and others. These ubiquitous HSPs are found in nearly all living organisms and many of them have a chaperon function, whereby they help ensure the proper folding of new proteins that may be formed as a result of stress. Protein misfolding can result in permanent damage, including irreversible neurological damage. In addition to protecting cells against damage caused by inflammation, HSPs assure proper folding of new proteins and destroy misfolded proteins.

During periods of disease, HSP production may be upregulated to prevent pathology-related damage. HSP is also upregulated in response to the accumulated stress of aging. Certain HSPs can produce extracellular messengers called chaperonins to aid in modulating the immune responses of the CNS. Since HSPs are able to modulate the body’s natural immune system, they may have specific neuroprotective benefits. For these reasons, HSPs have been the subject of scientific attention as they may be able to play an important therapeutic role in the treatment of neurodegenerative diseases [105].

Erythropoietin (EPO) is a cytokine secreted primarily by the kidneys and liver which has certain cytoprotective actions in the brain, protecting it from inflammatory and neurodegenerative assaults. An intranasal formulation of erythropoietin has been developed and is marketed as Neuro-EPO. Neuro-EPO was evaluated for its neuroprotective properties in a transgenic mouse model of Alzheimer’s disease [106]. Low-dose Neuro-EPO was able to restore deficits in memory, learning, and the recognition of new objects. In addition, it reduced neuroinflammation, apoptosis induction, OS, and amyloid load along with alleviating altered memories.

Thyrotropin-releasing hormone (TRH) is synthesized by the hypothalamus and confers neuroprotective benefits. Spontaneous cyclization of TRH produces His-Pro, a cyclic dipeptide. Cyclo(His-Pro), the cyclic dipeptide histidyl-proline, can be synthesized de novo endogenously and has been found throughout the body, in particular in the CNS, blood, and gastrointestinal tract. Cyclo(His-Pro) regulates glial cells and can cross the blood–brain barrier. In the brain, cyclo(His-Pro) can affect a variety of inflammatory and stress responses because of its effect on the Nrf2–NF-κB signaling axis. It has been hypothesized that cyclo(His-Pro) has the ability to interfere with many of the biological processes driving neurodegeneration and may be an important substance to study for the potential restoration of neuronal integrity. Cyclo(His-Pro) is also being studied for its possible role in the treatment of ALS [107].

Guanine nucleotide-binding proteins (G proteins), part of a large family of GPPase enzymes, transmit signals of extracellular origin to the cell’s interior. A G protein is able to bind to guanosine triphosphate (GTP), which essentially opens the signaling switch; when they bind to guanosine diphosphate (GDP), the switch is turned off. Regulators of G-protein signaling (RGS) were first thought to use the proteins that accelerated the GRPase processes in order to act as negative regulators of G-protein-coupled receptor signaling. All RGS proteins contain some conserved RGS domain, but the size and regulatory functions of the domain vary. Among the many RGS proteins, RGS1 and RGS10 are relatively small and are involved in the inflammatory and autoimmunological responses in the peripheral and central nervous systems. RGS1 and RGS10 may be important targets for future drug development for anti-inflammatory interventions that might stem neurodegenerative progression [108]. RGS1 and RGS10 are of particular interest for treatment of multiple sclerosis and Parkinson’s disease.

Chitosan is an abundant polysaccharide with antioxidant properties and little cytotoxicity. In a rat model of Aβ1–42-induced Alzheimer’s disease, chitosan oligosaccharides inhibited OS and neuroinflammatory response and thus conferred improvements in cognitive deficits as shown by the water maze and passive-avoidance tests [109]. The antioxidative properties of COS in the hippocampus were evaluated biochemically including their effects on apoptosis (TUNEL assay) and variations in inflammatory mediators (immunohistochemistry). When COS were administered to these rats at doses of 200, 400, or 800 mg/kg, the COS effectively reduced deficits in learning and memory. Neuronal apoptosis was ameliorated at these same doses. In this study, the neuroprotection conferred by COS aligned closely with OS inhibition, as shown by the evidence of diminishing levels of malondialdehyde, 8-hydroxy-2′-deoxyguanosine and increasing levels of glutathione peroxidase along with superoxide dismutase activities. It appears that by reducing the release of pro-inflammatory cytokines, such as IL-1β and TNFα, chitosan oligosaccharides may suppress the inflammatory response and decrease quantifiable signs of inflammation [109].

IL-8 is a cytokine that is produced by many types of normal cells, including neutrophils and macrophages; IL-8 is then stored in endothelial cells. IL-8 ligands bind to the CXCR1 and CXCR2 receptors and trigger various biological functions. The binding of IL-8 to CXCR2 contributes to the chemotactic responses seen in Alzheimer’s disease. A murine model of Aβ1–42-induced Alzheimer’s disease was used to evaluate the pharmacological antagonism of CXCR2 with SB332235 as a means to inhibit receptor-mediated inflammatory reactivity and, in that way, improve neuronal viability [110]. This competitive CXCR2 antagonist significantly reduced the expression of CXCR2 and microgliosis but left astrogliosis unaltered. This implies that CXCR2-dependent inflammatory responses may play a key role in induced Alzheimer’s disease in rats. Thus, the pharmacological modulation of this receptor may inhibit inflammatory reactivity, providing neuroprotection against oxidative damage [110].

The CNS is replete with nAChRs that are expressed in both neurons and non-neuronal cells. These nAChRs are receptor polypeptides that respond to endogenous acetylcholine and their activity is involved in numerous physiological functions, such as memory, learning, ambulation, attention, and others. The α7 subtype of nAChR may be involved in neuroprotection, synaptic plasticity, and neuronal survival. As such, it is a therapeutic target for numerous neurological disorders. When α7-nAChR is activated, it opens an anti-inflammatory pathway that appears to be related to the recruitment and activation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathways. JAK2/STAT3 pathways are involved in NF-κB nuclear translocation but can also help to regulate OS via the Nrf2/HO-1 axis [111].

Stem cells for human exfoliated deciduous teeth (SHEDs) were used to produce a serum-free conditioned medium applied in a mouse model of Alzheimer’s disease. The SHEDs were administered intranasally to mice which demonstrated substantial improvement in cognitive function. The conditioned medium made from SHED was found to contain factors involved in several neurological processes such as neuroprotection, axonal elongation, neurotransmission, inflammatory suppression, and the regulation of microglia. SHED conditioned medium attenuated pro-inflammatory effects caused by β-amyloid plaques, triggered the induction of certain anti-inflammatory microglia, and overall helped to create an anti-inflammatory environment suitable for tissue regeneration [112].

Nootropics are natural or synthetic drugs aimed at improving mental capacity. Piracetam, a synthetic derivative of gamma-aminobutyric acid (GABA), is a first-generation prototype nootropic drug. Piracetam remains enigmatic in that its mechanism of action remains unknown; it does not have an effect similar to GABA. In the cortical myoclonus, piracetam is anti-myoclonic [113]. Piracetam has been recommended for enhancing mental capacity and has been used to aid learning and sharpen memory [114]. Piracetam has been used for pediatric patients to treat breath-holding spells [115], epilepsy [116], and autism spectrum disorders where improvements were noted in a pediatric subpopulation [117]. Piracetam-induced neuroprotection remains to be elucidated; the possible role of a caspase-independent pathway has been investigated and it appears that piracetam may confer protection against LPS-induced inflammatory responses and apoptosis [118]. Piracetam appears to have antioxidative, anti-apoptotic, and neuroprotective actions against mitochondria.

Fasudil is a calcium channel blocker and vasodilator that works by inhibiting the Rho kinase isoforms (ROCK1 and ROCK2). Fasudil has been used to treat cerebral vasospasm, such as might occur in a subarachnoid hemorrhage, and to ameliorate the cognitive decline associated with stroke [119]. Since the ROCK pathways are involved in the dopaminergic neuronal degeneration, fasudil may be a potential therapeutic agent to treat Parkinson’s disease. In a mouse model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), fasudil was tested for its effectiveness in treating dopaminergic neuron injury [120]. Fasudil demonstrated neuroprotective benefits against dopaminergic neurons and facilitated the recovery of motor function in the MPTP mice and suppressed inflammatory responses (IL-1β, TNFα, NF-κB-p6, and TLR-2), and reduced OS (iNOS and gp91Phox). The reduction in OS might be associated with enzymatic inhibition of ROCK or glycogen synthase kinase-3β or both. Microglial activation in the CNS can be either neuroprotective, on the one hand, or pro-inflammatory, on the other. To better describe these diverse actions, the phenotypes microglia M1 (pro-inflammatory) and M2 (neuroprotective) have been described, but have yet to be fully elucidated. It has been observed that M1 and M2 phenotypes can change with time, disease progression, and other factors. Administration of fasudil can shift microglia M1 to microglia M2, that is transition the microglial environment from a pro-inflammatory and potentially cytotoxic state to one of neuroprotection. Fasudil may also optimize the expression of antioxidative factors [119].

Growth factors are substances required to stimulate growth in living cells and may include vitamins and hormones. Growth factors may also help mediate neuroprotection. In a rodent model of Parkinson’s disease, plasma rich in growth factors (PRGF) under the brand name Endoret was administered as a moderator the inflammatory response. Endoret offered neuroprotection in this animal model of Parkinson’s disease by decreasing the inflammatory response and improving motor abilities. These benefits were associated with a marked decrease in NF-κB activation as well as reduced expression of nitric oxide, COX-2, and TNFα in the substantia nigra. It has been hypothesized that PRGF (Endoret) may be able to prevent dopaminergic degeneration by way of an NF-κB-dependent signaling process [121].

Glia maturation factor (GMF) is one of several neurotrophic factors that are involved in the development and proper function of the nervous and immune systems. Altered GMF expression can have a direct impact on the production of reactive oxygen species and inflammatory mediators, which are produced by the 1-methyl-4-phenylpyridinium (MPP+) by way of NF-κB. In GMF knockout neurons and glia, the lack of GMF led to a decrease in the production of reactive oxygen species and the downregulation of NF-κB-mediated production of TNFα and IL-1β compared to wild-type neurons and glia. The overexpression of GMF induced dopamine-related neurodegeneration, while the downregulation of GMF (by GMF-specific sharp-hairpin RNA) conferred neuroprotection from the toxic effects induced by MPP. In summary, it appears that a deficiency in GMF improves the antioxidant balance, as evidenced by observed decreased lipid peroxidation levels, less reactive oxygen species, and increased levels of glutathione. Furthermore, GMF deficiency also attenuated the dopamine-associated neuronal loss by downregulating the inflammatory responses mediated by way of the NF-κB pathways [122]. GMF appears to play a role in mediating OS and the release of MPP+, both of which can result in the loss of dopamine neurons.

Conditioned medium prepared from human adipose-derived mesenchymal stem cells (CM-hMSCA) has been developed with the goal of offering therapeutic benefit in neuropathological conditions. The concept behind CM-hMSCA is to offer protection to astrocytes so that they can maintain their neuroprotective functions. In a model of human astrocytes with scratch injury, CM-hMSCA was shown to regulate cytokines IL-2, IL-6, IL-8, IL-10, granulocyte–macrophage colony-stimulating factor, and TNFα. Moreover, CM-hMSCA downregulates calcium (at the cytoplasmic level), mitochondrial dynamics, and the mitochondrial respiratory chain. CM-hMSCA can also modulate the expression of any number of proteins involved in several signaling pathways, such as the AKT/pAKT and ERK1/2/pERK. CM-hMSCA may also be able to mediate the cellular-level localization of neuroglobin, an intracellular hemoprotein expressed mainly in the central and peripheral nervous systems. These observations strongly suggest that CM-hMSCA holds promise as a potential protective agent for astrocytes in patients with brain pathology [123].

Glucagon-like peptide 1 (GLP-1) is an incretin hormone produced in the gut as a product of pre-proglucagon, a polypeptide that splits to produce numerous hormones that are similar to the parent (hence the name “glucagon-like”). One role of incretins is to enhance the synthesis and secretion of insulin from the pancreas in response to food. Originally, it was thought that GLP-1 was mainly related to insulin but it is now clear that in addition to glucose control, it has multiple additional functions in the brain, heart, and kidney. Both GLP-1 and GLP-1 receptor agonists have antioxidative properties that make them effective in the treatment of certain chronic diseases, such as diabetes. The activation of GLP-1 receptor signaling may enhance neurogenesis, reduce apoptosis, and protect neuronal function, making it a promising area for further study in the treatment of neurodegenerative diseases [124].

Calycosin belongs to the class of 7-hydroxyisoflavones and is extracted from the dry root of the Radix Astragali plant used in traditional Chinese medicine. Calycosin is the main bioactive chemical of this plant and acts like a typical phytoestrogen by binding to estrogen receptors. It has been shown to improve cognitive impairment caused by diabetes mellitus, which suggests that it might improve cognitive function in patients with Alzheimer’s disease. Using APP/PSO transgenic mice as a model for Alzheimer’s disease, investigators intraperitoneally injected the animals with three different doses of calycosin (10, 20, and 40 mg/kg) [125]. In these mice, calycosin mitigated OS and activated the protein kinase C pathway, reducing the inflammatory response in the hippocampus and improving cognition.

Age- and lifestyle-related changes in metabolism are often a result of increases in OS and inflammation, factors facilitating metabolic dysfunction and cognitive decline [126, 127]. Changes in insulin, leptin, and amylin resulting from poor diet, aging, or metabolic disease can result in cognitive decline and contribute to the development of AD [129‐131]. Therefore, therapies that aim to return these metabolic systems to a homeostatic state hold the highest therapeutic potential for the subsequent treatment of both metabolic and cognitive diseases [132].

Advanced glycation end products (AGEs) are potentially harmful compounds that accumulate with advancing age. AGEs can be produced endogenously or assumed with the diet. AGEs are associated with the pathogenesis of neuronal deficits observed in diabetes. Hyperglycemia accelerates and increases the production of AGEs, and high levels of AGE may be associated with premature aging and any number of diseases, including Alzheimer’s disease, heart disease, and kidney failure. Rosiglitazone is an antidiabetic drug that can be described as a peroxisome proliferator-activated receptor gamma (PPARγ). Rosiglitazone belongs to a family of ligand-activate nuclear receptors and its ligands are associated with a variety of physiological, pathological, and inflammatory pathways. AGEs are suspected of playing a role in the neuronal impairment that is associated with diabetes mellitus; rosiglitazone appears effective against AGE-mediated neurotoxicity on human neural stem cells. Rosiglitazone can activate PPARγ-dependent signaling, which has been shown to confer neuroprotection in AGE-treated human neural stem cells. This implies that there may be a role for PPARγ ligands in the treatment of neurodegenerative disorders [133].

Silver nanoparticles (AgNPs) are actually predominantly silver oxide in the form of particles ranging in size from about 1 to 100 nm. These silver nanoparticles have antibacterial properties and are used in a variety of consumer and medical products. Neural cells can uptake nanoparticles in the size range of 3–5 nm. The potential effects of silver nanoparticles on gene expression related to inflammation and neurodegeneration was studied in murine brain ALT astrocytes, microglial BV2 cells, and neuron N2a cells [134]. After being exposed to silver nanoparticles at doses of 5, 10, and 12.5 μg/ml, the neural cells showed a marked increase in secretion of IL-1β and induced gene expression of C-X-C motif chemokine 13 (CXCL13), macrophage receptor with collagenous structure, and glutathione synthetase [134]. This study also found that after treatment with silver nanoparticles, amyloid-β plaques (a pathological feature of Alzheimer’s disease) were deposited in neural cells. Following exposure to silver nanoparticles, gene expression of the amyloid precursor protein was induced. By the same token, protein levels, neprilysin, and low-density lipoprotein receptor were decreased in neural cells. The results from this study suggest that silver nanoparticles may be able to alter gene and protein expression related to amyloid-β deposition and could potentially induce the neurodegeneration of Alzheimer’s disease [134]. Further study is warranted.

The role of immunomodulation is changing medicine and it has been suggested that immunomodulatory pharmacological agents might be an early intervention for patients with clinical signs of Parkinson’s disease or even as a prophylactic treatment in patients at elevated risk for developing Parkinson’s disease [18]. Murine studies have shown that various immunomodulators could reduce motor deficits and alleviate dopaminergic neurotoxic effects. Some, but not all, immunomodulators have an anti-inflammatory action, decrease OS, and reduce the products of lipid peroxidation. They may also decrease the activities of microglia and astrocytes and decrease the infiltration of T cells into the substantia nigra. When animals with brain lesions were pretreated with fingolimod, tanshinone I, dimethyl fumarate, thalidomide, or cocaine- and amphetamine-regulated transcript peptide, this prophylaxis ameliorated motor deficits and nigral dopaminergic neurotoxicity [18].

More specifically:

Fingolimod or FTY720 reduced functional motor deficits and reduced the loss of TH⁺ neurons in the substantia nigra. It also attenuated the decrease of striatal dopamine and its metabolite levels [91].

Tanshinone I ameliorated the dopaminergic neurotoxicity in the substantia nigra and striatum and protected the striatum from OS by increasing glutathione levels [135].

Tanshinone IIA reduced apomorphine-induced contralateral rotations and alleviated the loss of TH⁺ neurons in the substantia nigra and striatum. It also attenuated the reduction of dopamine and its metabolites [136, 137].

Dimethyl fumarate reduced motor deficits while protecting dopaminergic neurons in the substantia nigra against α-syn toxicity. It likewise decreased microgliosis and astrogliosis [138, 139].

Lenalidomide was shown to improve motor deficits and improve dopamine fiber loss in the striatum, together with a decrease in microgliosis in the striatum and hippocampus. It also reduced the expression of certain proinflammatory cytokines, namely TNFα, IL-6, IL-1β, and IFN-γ and increased the expression of the anti-inflammatory cytokines IL-10 and IL-13 [140].

Thalidomide, like lenalidomide, restored dopamine fiber loss in the striatum, and reduced the expression of TNFα, IL-6, IL-1β, and IFN-γ [140].

Ginsenoside Rg1 decreased dopaminergic neuronal loss in the substantia nigra. The regulatory T cells in the blood were increased and the serum levels of TNFα, IFN-γ, IL-1β, and IL-6 were reduced. Microgliosis was inhibited and infiltration of CD3⁺ T cells into the substantia nigra was also reduced [141].

CNI-1493 attenuated dopaminergic cell loss in the substantia nigra, alleviated striatal loss of dopamine content, and reduced microgliosis in the substantia nigra [142].

Pycnogenol improved behavioral motor deficits [143].

Cyclosporin enhanced motor and cognitive function, decreased the striatal level of human α-syn and partially restored the level of TH protein, exhibited an anti-inflammatory effect by lowering the expression level of NFATc3 and alleviated mitochondrial stress in the midbrain [144].

Acetoside reduced parkinsonism symptoms [145].

SA00025 was partially neuroprotective of dopaminergic neurons and fibers. It also brought about changes in microglial morphology, indicative of a resting state and a decrease in reactive microglia. The astrocyte GFAP staining intensity in the substantia nigra and IL-6 levels were also decreased [146].

C5aR antagonist DF3016A. Complement (C) membrane receptors and proteins are constitutively expressed by the CNS. Part of it is the C5a, which represents the terminal effector of the C cascade. This part is mostly involved in pain and neuroinflammation, with several clinical consequences [147]. Recently, a novel selective C5aR antagonist (DF3016A) has shown the capacity to protect the neurons against a neuroinflammation-related process, in an animal model [148]. This could represent a new therapeutic approach to controlling CNS neuroinflammatory conditions and neurodegeneration due to OS.