Neuroprotective Effects of Silymarin and Silibinin: A Review of Mechanisms in Common Neurodegenerative Diseases, Cerebral Ischemia, and Diabetic Neuropathy

Parkinson’s disease (PD) involves aggregation of α-synuclein and progressive loss of dopaminergic neurons. Pathogenesis of PD may also be related to one’s genetic background. PD is most common among geriatric population and approximately 1–2% of population suffers over age 65 years. Currently no successful therapies are in practice for the management of PD and available therapies tend to decrease the symptoms of PD only. Furthermore, these are associated with diverse range of adverse effects profile. The neuroprotective effects of polyphenols are widely studied and documented. Among phytochemicals, silymarin is one of the most widely used flavonoids because of its extensive therapeutic properties and has been indicated in pathological conditions of prostate, CNS, lungs, skin, liver, and pancreas. Silymarin is a mixture of flavonolignans (silybin, isosilybin, and silychristin), small amount of flavonoids (taxifolin), fatty acids, and other polyphenolic compounds extracted from the dried fruit of Silybum marianum and is clinically used for hepatoprotective effects since ancient times. Neuroprotective effects of silymarin have been studied in various models of neurological disorders such as Alzheimer’s disease, PD, and cerebral ischemia. The aim of the present study is to provide a comprehensive review of the recent literature exploring the effects of silymarin administration on the progression of PD. Reducing oxidative stress, inflammatory cytokines, altering cellular apoptosis machinery, and estrogen receptor machinery are mechanisms that are responsible for neuroprotection by silymarin, as discussed in this review. Additionally, because of poor aqueous solubility, the bioavailability of silymarin is low and only 23–47% of silymarin reaches systemic circulation after oral administration. Our primary focus is on the chemical basis of the pharmacology of silymarin in the treatment of PD and its mechanisms and possible therapeutic/clinical status while addressing the bioavailability limitation.

Background:Adult-onset neurodegenerative diseases affect millions and negatively impact health care systems worldwide. Evidence suggests that air pollution may contribute to aggravation of neurodegeneration, but studies have been limited.Objective:We examined the potential association between long-term exposure to particulate matter in aerodynamic diameter [fine particulate matter ()] and disease aggravation in Alzheimer’s (AD) and Parkinson’s (PD) diseases and amyotrophic lateral sclerosis (ALS), using first hospitalization as a surrogate of clinical aggravation.Methods:We used data from the New York Department of Health Statewide Planning and Research Cooperative System (SPARCS 2000–2014) to construct annual county counts of first hospitalizations with a diagnosis of AD, PD, or ALS (total, urbanicity-, sex-, and age-stratified). We used annual concentrations estimated by a prediction model at a resolution, which we aggregated to population-weighted county averages to assign exposure to cases based on county of residence. We used outcome-specific mixed quasi-Poisson models with county-specific random intercepts to estimate rate ratios (RRs) for a 1-y exposure. We allowed for nonlinear exposure–outcome relationships using penalized splines and accounted for potential confounders.Results:We found a positive nonlinear association that plateaued above (, 95% CI: 1.04, 1.14 for a increase from 8.1 to ). We also found a linear positive association (, 95% CI: 1.01, 1.09 per increase), and suggestive evidence of an association with AD. We found effect modification by age for PD and ALS with a stronger positive association in patients of age but found insufficient evidence of effect modification by sex or urbanization level for any of the outcomes.Conclusion:Our findings suggest that annual increase in county-level concentrations may contribute to clinical aggravation of PD and ALS. Importantly, the average annual concentration in our study was , below the current American national standards, suggesting the standards may not adequately protect the aging population. https://doi.org/10.1289/EHP7425

Aim of the present study is to investigate the effect of silymarin (SM), a potent antioxidant and anti-inflammatory compound on experimentally-induced Diabetic Neuropathy (DN) in male Wistar rats. Diabetes was induced by single streptozotocin (STZ) injection in rats. Pain-related behavior tests were performed including tail flick, paw-pressure analgesia and Rota-rod performance. Silymarin treatment was started after 21st day of diabetes induction and continued for 6 consecutive weeks. In serum fasting glucose, insulin, tumor necrosis factor-&alpha (TNF-α), interleukin-6 (IL-6) and interleukin-1&beta (IL-1&beta) levels were estimated and in sciatic nerve, thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), Superoxide Dismutase (SOD), catalase (CAT), glutathione-s-transferase (GST), glutathione-reductase (GR) and glutathione peroxidase (GSH-Px) activities were measured. Diabetic rats developed neuropathy which was apparent from decreased tail-flick latency and paw-withdrawal latency.This was escorted by decreased motor coordination as assessed by performance on Rota-rod treadmill. Treatment with SM ameliorated the hyperalgesia, analgesia and improved motor coordination. STZ significantly increased TBARS and decreased GSH levels in sciatic nerve where silymarin treatment significantly protected those changes. Enzymatic activities such as SOD, CAT, GST, GSH-Px and GR were significantly inhibited in sciatic nerve of diabetic rats. The SM treatment significantly ameliorated decrease in antioxidant defense. Our results clearly demonstrate protective effect of SM is mediated through attenuation of oxidative stress and suggest therapeutic potential of SM in attenuation of diabetic neuropathy.

Occupational exposures to magnetic fields and neurodegenerative disease risks

Dysregulation of microRNA gene expression has been implicated in many neurodegenerative diseases, including Parkinson's disease. However, the individual dysregulated microRNAs remain largely unknown. Previous meta-analyses have highlighted several microRNAs being differentially expressed in post-mortem Parkinson's disease and Alzheimer's disease brains versus controls, but they were based on small sample sizes. In this study, we quantified the expression of the most compelling Parkinson's and Alzheimer's disease microRNAs from these meta-analyses ('candidate miRNAs') in one of the largest Parkinson's/Alzheimer's disease case-control post-mortem brain collections available (n = 451), thereby quadruplicating previously investigated sample sizes. Parkinson's disease candidate microRNA hsa-miR-132-3p was differentially expressed in our Parkinson's (P = 4.89E-06) and Alzheimer's disease samples (P = 3.20E-24) compared with controls. Alzheimer's disease candidate microRNAs hsa-miR-132-5p (P = 4.52E-06) and hsa-miR-129-5p (P = 0.0379) were differentially expressed in our Parkinson's disease samples. Combining these novel data with previously published data substantially improved the statistical support (α = 3.85E-03) of the corresponding meta-analyses, clearly implicating these microRNAs in both Parkinson's and Alzheimer's disease. Furthermore, hsa-miR-132-3p/-5p (but not hsa-miR-129-5p) showed association with α-synuclein neuropathological Braak staging (P = 3.51E-03/P = 0.0117), suggesting that hsa-miR-132-3p/-5p play a role in α-synuclein aggregation beyond the early disease phase. Our study represents the largest independent assessment of recently highlighted candidate microRNAs in Parkinson's and Alzheimer's disease brains, to date. Our results implicate hsa-miR-132-3p/-5p and hsa-miR-129-5p to be differentially expressed in both Parkinson's and Alzheimer's disease, pinpointing shared pathogenic mechanisms across these neurodegenerative diseases. Intriguingly, based on publicly available high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation data, hsa-miR-132 may interact with SNCA messenger RNA in the human brain, possibly pinpointing novel therapeutic approaches in fighting Parkinson's disease.

The Role of NAC in Amyloidogenesis in Alzheimer's Disease

Olfactory proteotyping: towards the enlightenment of the neurodegeneration

Activation of Nrf2 signaling as a common treatment of neurodegenerative diseases.

Neurodegenerative procedures include a large spectrum of disorders with diverse pathological features and clinical manifestations, such as Alzheimer's Disease (AD), Parkinson's disease (PD), Multiple sclerosis, and Amyotrophic lateral sclerosis (ALS). Neurodegenerative diseases (NDs) are indicated by progressive loss of neurons and cognitive function, which is associated with free radical formation, extra and intercellular accumulation of misfolded proteins, oxidative stress, mitochondrial and neurotrophins dysfunction, bioenergetic impairment, inflammation, and apoptotic cell death. Boswellic acid is a pentacyclic triterpene molecule of plant origin that has been applied for treating several inflammatory disorders. Numerous studies have also investigated its' therapeutic potential against multiple NDs. In this article, we aim to review the neuroprotective effects of boswellic acid on NDs and the related mechanisms of action. The databases of PubMed, Google Scholar, Web of Sciences, and Scopus were searched to find studies that reported the effects of boswellic acid on NDs without time limits. Review articles, letters, editorials, unpublished data, and articles not published in the English language were not included in the study. Overall, 17 studies were included in the present study (8 NDs in general, 5 AD, 3 PD, and 1 ALS). According to the reports, boswellic acid exerts anti-inflammatory, antioxidant, antiapoptotic, and neuromodulatory effects against NDs. Boswellic acid decreases Tau phosphorylation and amyloid-β (Aβ) generation in AD. This substance also protects nigrostriatal dopaminergic neurons and improves motor impairments in PD and modulates neurotransmitters, decreases the demyelination region, and improves behavioral functions in ALS. Due to the significant effects of boswellic acid in NDs, more clinical studies are necessary to evaluate the pharmacokinetics of this substance because it seems that boswellic acid can be used as a complementary or alternative treatment in patients with NDs.

Editorial: A Trends guide to Neurodegenerative Disease and Repair

Silymarin, a C25 containing flavonoid from the plant Silybum marianum, has been the gold standard drug to treat liver disorders associated with alcohol consumption, acute and chronic viral hepatitis, and toxin-induced hepatic failures since its discovery in 1960. Apart from the hepatoprotective nature, which is mainly due to its antioxidant and tissue regenerative properties, Silymarin has recently been reported to be a putative neuroprotective agent against many neurologic diseases including Alzheimer's and Parkinson's diseases, and cerebral ischemia. Although the underlying neuroprotective mechanism of Silymarin is believed to be due to its capacity to inhibit oxidative stress in the brain, it also confers additional advantages by influencing pathways such as β-amyloid aggregation, inflammatory mechanisms, cellular apoptotic machinery, and estrogenic receptor mediation. In this review, we have elucidated the possible neuroprotective effects of Silymarin and the underlying molecular events, and suggested future courses of action for its acceptance as a CNS drug for the treatment of neurodegenerative diseases.

This Special Issue comprises nine reviews offering perspectives from the development of neurodegeneration in different pathologies to neuronal protection, providing new views on the mechanism of neurodegeneration and associated processes and a summary of the progress in neuroscience. We hope you find these reviews interesting and informative and we thank the authors for these excellent contributions to The FEBS Journal.

Oxidative stress contributes to the progression of neurodegenerative diseases of the central and peripheral nervous systems, including Alzheimer's disease, Parkinson's disease, stroke, and diabetic neuropathy. Despite the greater capability of peripheral nerves to regenerate compared with those in the brain or spinal cord, chronic oxidative stress leads to irreversible neurodegeneration in peripheral nerves. Thus, many efforts have been made to defend against irreversible peripheral nerve degeneration and oxidative stress. Numerous phytochemicals have been revealed as antioxidants which neutralize free radicals and reduce peripheral neurocellular damage. Among them, polyphenols alleviate neurodegeneration by interacting with reactive oxygen species. Apigenin is a polyphenol found in plant-derived foods, including parsley, thyme, celery, and chamomile tea. Apigenin has been reported to exert antioxidative effects by scavenging free radicals. In particular, apigenin has a neuroprotective effect against oxidative stress in neurological disorders, such as cerebral ischemia. However, to date, no studies have shown an association of the inhibitory effect of apigenin with peripheral nerve degeneration. In this work, we showed that apigenin has a neuroprotective effect against peripheral nerve degeneration according to four key phenotypes: axonal degradation, myelin fragmentation, trans-dedifferentiation, and proliferation of Schwann cells via Krox20- and extracellular signal-regulated kinase-independent processes. Thus, apigenin could be a good candidate to treat peripheral neurodegenerative diseases.

Glutamate-induced excito-neurotoxicity likely contributes to non-cell autonomous neuronal death in neurodegenerative diseases. Microglial clearance of dying neurons and associated debris is essential to maintain healthy neural networks in the central nervous system. In fact, the functions of microglia are regulated by various signaling molecules that are produced as neurons degenerate. Here, we show that the soluble CX3C chemokine fractalkine (sFKN), which is secreted from neurons that have been damaged by glutamate, promotes microglial phagocytosis of neuronal debris through release of milk fat globule-EGF factor 8, a mediator of apoptotic cell clearance. In addition, sFKN induces the expression of the antioxidant enzyme heme oxygenase-1 (HO-1) in microglia in the absence of neurotoxic molecule production, including NO, TNF, and glutamate. sFKN treatment of primary neuron-microglia co-cultures significantly attenuated glutamate-induced neuronal cell death. Using several specific MAPK inhibitors, we found that sFKN-induced heme oxygenase-1 expression was primarily mediated by activation of JNK and nuclear factor erythroid 2-related factor 2. These results suggest that sFKN secreted from glutamate-damaged neurons provides both phagocytotic and neuroprotective signals.

Some philosophical aspects of Alzheimer's discovery: an American perspective.- The aging brain and its disorders.- Epidemiology of Alzheimer's disease.- Descriptive and analytic epidemiology of Alzheimer's disease.- A proposed classification of familial Alzheimer's disease based on analysis of 32 multigeneration pedigrees.- Morphology of Alzheimer's disease and related disorders.- Morphology of white matter, subcortical, dementia in Alzheimer's disease.- Morphology of the cerebral cortex in relation to Alzheimer's dementia.- Quantitative investigations of presenile and senile changes of the human entorhinal region.- Neuronal plasticity of the septo-hippocampal pathway in patients suffering from dementia of Alzheimer type.- Morphology of neurofibrillary tangles and senile plaques.- An in vitro model for the study of the neurofibrillary degeneration of the Alzheimer type.- Molecular and cellular changes associated with neurofibrillary tangles and senile plaques.- Brain abnormalities in aged monkeys: a model sharing features with Alzheimer's disease.- Aged dogs: an animal model to study beta-protein amyloidogenesis.- Immunocytochemical and ultrastructural pathology of nerve cells in Alzheimer's disease and related disorders.- Choline-acetyltransferase immunoreactivity in the hippocampal formation of control subjects and patients with Alzheimer's disease.- Calbindin immunoreactive _eurons in Alzheimer-type dementia.- Lactate production and glycolytic enzymes in sporadic and familial Alzheimer's disease.- Impairment of cerebral glucose metabolism parallels learning and memory dysfunctions after intracerebral streptozotocin.- Choline levels, the regulation of acetylcholine and phosphatidylcholine synthesis, and Alzheimer's disease.- Acetylcholine synthesis and membrane phospholipids.- Hippocampal and cardiovascular effects of muscarinic agents.- Cholinergie and monoaminergic neuromediator systems in DAT. Neuropathological and neurochemical findings.- Alterations in catecholamine neurons in the locus coeruleus in dementias of Alzheimer's and Parkinson's disease.- Tyrosine hydroxylase, tryptophan hydroxylase, biopterin and neopterin in the brains and biopterin and neopterin in sera from patients with Alzheimer's disease.- Postreceptorial enhancement of neurotransmission for the treatment of cognitive disorders.- Excitatory dicarboxylic amino acid and pyramidal neurone neurotransmission of the cerebral cortex in Alzheimer's disease.- The sequence within the two polyadenylation sites of the A4 amyloid peptide precursor stimulates the translation.- Alzheimer-like changes of cortical amino acid transmitters in elderly Down's syndrome.- Characteristics of learning deficit induced by ibotenic acid lesion of the frontal cortex in rats.- Memory loss by glutamate antagonists: an animal model of Alzheimer's disease?.- Convulsant properties of methylxanthines, potential cognitive enhancers in dementia syndromes.- Neurodegenerative diseases: CSF amines, lactate and clinical findings.- Somatostatin-like immunoreactivity and neurotransmitter metabolites in the cerebrospinal fluid of patients with senile dementia of Alzheimer type and Parkinson's disease.- Nerve growth factor in serum of patients with dementia (Alzheimer type).- Neuroendocrine dysfunction in early-onset Alzheimer's disease.- Urinary excretion of salsolinol enantiomers and 1,2-dehydrosalsolinol in patients with degenerative dementia.- Alzheimer's disease - one, two or several?.- Diagnostic criteria of Alzheimer's disease.- Clinical diagnosis of Alzheimer's disease: DSM-III-R, ICD-10 - what else?.- Clinical aspects and terminology of dementing syndromes.- Symptoms of depression in the course of multi-infarct dementia and dementia of Alzheimer's type.- Cognitive deterioration and dementia outcome in depression: the search for prognostic factors.- Diagnostic significance of language evaluation in early stages of Alzheimer's disease.- The Alzheimer patient in the family context: how to help the family to cope.- Towards a clinically specific profile of severe senile primary degenerative dementia of the Alzheimer type (PDDAT).- Sequential clinical approach to differential diagnosis of dementia.- Do old patients with Down's syndrome develop premature brain atrophy?.- Results of EEG brain mapping and neuroimaging methods in Senile Dementia of Alzheimer's Typ (SDAT) and Vascular Dementia (VD).- Regulation of EEG delta activity by the cholinergic nucleus basalis.- EEG- and cognitive changes in Alzheimer's disease - a correlative follow-up study.- Decreased hippocampal metabolic rate in patients with SDAT assessed by positron emission tomography during olfactory memory task.- PET criteria for diagnosis of Alzheimer's disease and other dementias.- Oxygen metabolism in the degenerative dementias.- Positron emission tomography for differential diagnosis of dementia: a case of familial dementia.- Comparison between cerebral glucose metabolism and late evoked potentials in patients with Alzheimer's disease.- High resolution regional cerebral blood flow measurements in Alzheimer's disease and other dementia disorders.- Single photon emission computed tomography (SPECT) in Pick's disease: two case reports.- In vivo studies of hippocampal atrophy in Alzheimer's disease.- Outline for the evaluation of nootropic drugs.- Drug treatment of dementia.- Cognitive enhancing properties of antagonist ?-carbolines: new insights into clinical research on the treatment of dementias?.- Long term treatment of SDAT patients with pyritinol.- Listed in Current Contents.