Potent,Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors

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Neuroinflammation in Huntington’s Disease: A Starring Role for Astrocyte and Microglia

Huntington’s disease (HD) is a neurodegenerative genetic disorder caused by a CAG repeat expansion in the huntingtin gene. HD causes motor, cognitive, and behavioral dysfunction. Since no existing treatment affects the course of this disease, new treatments are needed. Inflammation is frequently observed in HD patients before symptom onset. Neuroinflammation, characterized by the presence of reactive microglia, astrocytes and inflammatory factors within the brain, is also detected early. However, in comparison to other neurodegenerative diseases, the role of neuroinflammation in HD is much less known. Work has been dedicated to altered microglial and astrocytic functions in the context of HD, but less attention has been given to glial participation in neuroinflammation. This review describes evidence of inflammation in HD patients and animal models. It also discusses recent knowledge on neuroinflammation in HD, highlighting astrocyte and microglia involvement in the disease and considering anti-inflammatory therapeutic approaches.     

Design and Evaluation of 3-(Benzylthio)benzamide Derivatives as Potent and Selective SIRT2 Inhibitors

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BACE1: A Key Regulator in Alzheimer’s Disease Progression and Current Development of its Inhibitors

Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disease with no specific disease-modifying treatment. β-secretase (BACE1) is considered the potential and rationale target because it is involved in the rate-limiting step, which produces toxic Aβ₄₂ peptides that leads to deposits in the form of amyloid plaques extracellularly, resulting in AD.Objective: This study aims to discuss the role and implications of BACE1 and its inhibitors in the management of AD.Methods: We have searched and collected the relevant quality work from PubMed using the following keywords “BACE1”, BACE2”, “inhibitors”, and “Alzheimer’s disease”. In addition, we included the work which discusses the role of BACE1 in AD and the recent work on its inhibitors.Results: In this review, we have discussed the importance of BACE1 in regulating AD progression and the current development of BACE1 inhibitors. However, the development of a BACE1 inhibitor is very challenging due to the large active site of BACE1. Nevertheless, some of the BACE1 inhibitors have managed to enter advanced phases of clinical trials, such as MK-8931 (Verubecestat), E2609 (Elenbecestat), AZD3293 (Lanabecestat), and JNJ-54861911 (Atabecestat). This review also sheds light on the prospect of BACE1 inhibitors as the most effective therapeutic approach in delaying or preventing AD progression.Conclusion: BACE1 is involved in the progression of AD. The current ongoing or failed clinical trials may help understand the role of BACE1 inhibition in regulating the Aβ load and cognitive status of AD patients.     

Biomonitoring of Mycotoxins in Plasma of Patients with Alzheimer’s and Parkinson’s Disease

Exposure to environmental contaminants might play an important role in neurodegenerative disease pathogenesis, such as Parkinson´s disease (PD) and Alzheimer´s disease (AD). For the first time in Spain, the plasmatic levels of 19 mycotoxins from patients diagnosed with a neurodegenerative disease (44 PD and 24 AD) and from their healthy companions (25) from La Rioja region were analyzed. The studied mycotoxins were aflatoxins B1, B2, G1, G2 and M1, T-2 and HT-2, ochratoxins A (OTA) and B (OTB), zearalenone, sterigmatocystin (STER), nivalenol, deoxynivalenol, 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol, deepoxy-deoxynivalenol, neosolaniol, diacetoxyscirpenol and fusarenon-X. Samples were analyzed by LC-MS/MS before and after treatment with β-glucuronidase/arylsulfatase in order to detect potential metabolites. Only OTA, OTB and STER were detected in the samples. OTA was present before (77% of the samples) and after (89%) the enzymatic treatment, while OTB was only detectable before (13%). Statistically significant differences in OTA between healthy companions and patients were observed but the observed differences might seem more related to gender (OTA levels higher in men, p-value = 0.0014) than the disease itself. STER appeared only after enzymatic treatment (88%). Statistical analysis on STER, showed distributions always different between healthy controls and patients (patients’ group > controls, p-value < 0.0001). Surprisingly, STER levels weakly correlated positively with age in women (rho = 0.3384), while OTA correlation showed a decrease of levels with age especially in the men with PD (rho = −0.4643).     

Recent Evidence in Epigenomics and Proteomics Biomarkers for Early and Minimally Invasive Diagnosis of Alzheimer’s and Parkinson’s Diseases

Background: Alzheimer’s (AD) and Parkinson’s diseases (PD) show deposits of improperly folded modified proteins. Protein expression mechanisms are involved since the early stages. Several studies evaluated epigenomics and proteomics profiles in these patients, with promising results. In general, they focused on early, specific, and minimally invasive biomarkers for the diagnosis and prognosis of AD and PD.Objectives This review aimed at summarizing results to find the most reliable evidence in the field.Results Among epigenomics studies, there is a focus on microRNAs (miRNAs) as candidate diagnostic biomarkers for AD or PD from blood samples like miR-342-3p, miR-107, miR-106a-5p, miR-106b-5p, miR-195, and miR-19b. In addition, DNA methylation has been tested in a few works, obtaining significant differences in some genes (NCAPH2/LMF2 COASY, SPINT1, BDNFTREM1, TREM2, NPAS2, PDE4D), which could be useful for evaluating the disease progression as well as potential risk factors. Regarding proteomics, most of the studies were untargeted and used plasma or serum samples. In general, they highlighted the importance of coagulation, inflammation pathways, and oxidative stress. Among targeted studies, some proteins (phosphorylated tau, C reactive protein (CRP), interleukins, necrosis factors, transferrin, glial fibrillary acidic protein (GFAP), and neurofilaments) showed different plasma levels in AD and PD patients in comparison with healthy participants. Finally, a few studies have identified specific-AD and PD epigenetic and proteomic biomarkers (ApoE and oxidized DJ-1) in comparison with other similar pathologies.Conclusion In general, there is a common lack of clinical validation of these potential biomarkers because of which its use in clinical practice is still limited.     

Inhibition of β-Amyloid Aggregation in Alzheimer’s Disease: The Key Role of (Pro)electrophilic Warheads

Catechols have been largely investigated as antiaggregating agents toward β-amyloid peptide. Herein, as a follow up of a previous series of hydroxycinnamic derivatives, we synthesized a small set of dihydroxy isomers for exploring the role of the reciprocal position of the two hydroxyl functions at a molecular level. Para- and ortho-derivatives effectively reduced amyloid fibrillization, while the meta-analogue was devoid of any activity in this respect. Electrochemical analyses showed that the antiaggregating potency correlates with the oxidation potential, hence indicating the proelectrophilic character as a prerequisite for activity. Interestingly, mass spectrometry studies and quantum mechanical calculations revealed different modes of action for active para- and ortho-derivatives, involving covalent or noncovalent interactions with β-amyloid. The distinctive mode of action is also translated into a different cytotoxicity profile. This work clearly shows how apparently minimal structural modifications can completely change the compound behavior and generate alternative mechanisms of action of proelectrophilic chemical probes.     

Ginsenoside Rg1 exerts neuroprotective effects in 3-nitropronpionic acid-induced mouse model of Huntington’s disease via suppressing MAPKs and NF-κB pathways in the striatum

Huntington’s disease (HD) is one of main neurodegenerative diseases, characterized by striatal atrophy, involuntary movements, and motor incoordination. Ginsenoside Rg1 (Rg1), an active ingredient in ginseng, possesses a variety of neuroprotective effects with low toxicity and side effects. In this study, we investigated the potential therapeutic effects of Rg1 in a mouse model of HD and explored the underlying mechanisms. HD was induced in mice by injection of 3-nitropropionic acid (3-NP, i.p.) for 4 days. From the first day of 3-NP injection, the mice were administered Rg1 (10, 20, 40 mg·kg⁻¹, p.o.) for 5 days. We showed that oral pretreatment with Rg1 alleviated 3-NP-induced body weight loss and behavioral defects. Furthermore, pretreatment with Rg1 ameliorated 3-NP-induced neuronal loss and ultrastructural morphological damage in the striatum. Moreover, pretreatment with Rg1 reduced 3-NP-induced apoptosis and inhibited the activation of microglia, inflammatory mediators in the striatum. We revealed that Rg1 exerted neuroprotective effects by suppressing 3-NP-induced activation of the MAPKs and NF-κΒ signaling pathways in the striatum. Thus, our results suggest that Rg1 exerts therapeutic effects on 3-NP-induced HD mouse model via suppressing MAPKs and NF-κΒ signaling pathways. Rg1 may be served as a novel therapeutic option for HD.     

Neuroinflammatory Signaling in the Pathogenesis of Alzheimer’s Disease

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the formation of intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques. Growing evidence has suggested that AD pathogenesis is not only limited to the neuronal compartment but also strongly interacts with immunological processes in the brain. On the other hand, aggregated and misfolded proteins can bind with pattern recognition receptors located on astroglia and microglia and can, in turn, induce an innate immune response, characterized by the release of inflammatory mediators, ultimately playing a role in both the severity and the progression of the disease. It has been reported by genome-wide analysis that several genes which elevate the risk for sporadic AD encode for factors controlling the inflammatory response and glial clearance of misfolded proteins. Obesity and systemic inflammation are examples of external factors which may interfere with the immunological mechanisms of the brain and can induce disease progression. In this review, we discussed the mechanisms and essential role of inflammatory signaling pathways in AD pathogenesis. Indeed, interfering with immune processes and modulation of risk factors may lead to future therapeutic or preventive AD approaches.     

Crocus Sativus L. (Saffron) in Alzheimer’s Disease Treatment: Bioactive Effects on Cognitive Impairment

Crocus sativus L. (saffron) appears to own neuroprotective effects on cognitive impairment in patients with Alzheimer’s disease (AD). The purpose of this work is to review evidence and mechanisms of saffron-induced therapeutic outcomes and measureable cognitive benefits in AD.The literature was reviewed, and preclinical and clinical studies were identified. In vitro and in vivo preclinical studies were selected according to these criteria: 1) development of saffron pharmacological profile on biological or biophysical endpoints; 2) evaluation of saffron efficacy using animal screens as an AD model, and 3) duration of the studies of at least 3 months. As for the clinical studies, the selection criteria included: 1) patients aged ≥ 60, 2) AD diagnosis according to National Institute on Aging-Alzheimer''s Association (NIAAA) criteria, and 3) appropriate procedures to assess cognitive, functional, and clinical status. A total of 1477 studies published until November 2020 were identified during an initial phase, of which 24 met the inclusion criteria and were selected for this review.Seventeen in vitro and in vivo preclinical studies have described the efficacy of saffron on cognitive impairment in animal models of AD, highlighting that crocin appears to be able to regulate glutamate levels, reduce oxidative stress, and modulate Aβ and tau protein aggregation. Only four clinical studies have indicated that the effects of saffron on cognitive impairment were not different from those produced by donepezil and memantine and that it had a better safety profile.Saffron and its compounds should be further investigated in order to consider them a safer alternative in AD treatment.     

Neuroprotective Effect of Astersaponin I against Parkinson’s Disease through Autophagy Induction

An active compound, triterpene saponin, astersaponin I (AKNS-2) was isolated from Aster koraiensis Nakai (AKNS) and the autophagy activation and neuroprotective effect was investigated on in vitro and in vivo Parkinson’s disease (PD) models. The autophagy-regulating effect of AKNS-2 was monitored by analyzing the expression of autophagy-related protein markers in SH-SY5Y cells using Western blot and fluorescent protein quenching assays. The neuroprotection of AKNS-2 was tested by using a 1-methyl-4-phenyl-2,3-dihydropyridium ion (MPP⁺)-induced in vitro PD model in SH-SY5Y cells and an MPTP-induced in vivo PD model in mice. The compound-treated SH-SY5Y cells not only showed enhanced microtubule-associated protein 1A/1B-light chain 3-II (LC3-II) and decreased sequestosome 1 (p62) expression but also showed increased phosphorylated extracellular signal–regulated kinases (p-Erk), phosphorylated AMP-activated protein kinase (p-AMPK) and phosphorylated unc-51-like kinase (p-ULK) and decreased phosphorylated mammalian target of rapamycin (p-mTOR) expression. AKNS-2-activated autophagy could be inhibited by the Erk inhibitor U0126 and by AMPK siRNA. In the MPP⁺-induced in vitro PD model, AKNS-2 reversed the reduced cell viability and tyrosine hydroxylase (TH) levels and reduced the induced α-synuclein level. In an MPTP-induced in vivo PD model, AKNS-2 improved mice behavioral performance, and it restored dopamine synthesis and TH and α-synuclein expression in mouse brain tissues. Consistently, AKNS-2 also modulated the expressions of autophagy related markers in mouse brain tissue. Thus, AKNS-2 upregulates autophagy by activating the Erk/mTOR and AMPK/mTOR pathways. AKNS-2 exerts its neuroprotective effect through autophagy activation and may serve as a potential candidate for PD therapy.     

Management Perspective of Wilson’s Disease: Early Diagnosis and Individualized Therapy

Wilson’s disease (WD) is an inherited disease caused by mutations in ATP7B and is characterized by the pathological accumulation of copper in the liver and brain. Common clinical manifestations of WD include a wide range of liver disease and neurological symptoms. In some patients, psychiatric symptoms may be the only manifestation at the time of diagnosis. The clinical features of WD are highly variable and can mimic any disease of internal medicine. Therefore, for unexplained medical diseases, the possibility of WD should not be ignored. Early diagnosis and treatment can improve the prognosis of WD patients and reduce disability and early death. Gene sequencing is becoming a valuable method to diagnose WD, and if possible, all WD patients and their siblings should be genetically sequenced. Copper chelators including D-penicillamine, trientine, and dimercaptosuccinic acid can significantly improve the liver injury and symptoms of WD patients but may have a limited effect on neurological symptoms. Zinc salts may be more appropriate for the treatment of asymptomatic patients or for the maintenance treatment of symptomatic patients. High-quality clinical trials for the drug treatment of WD are still lacking, therefore, individualized treatment options for patients are recommended. Individualized treatment can be determined based on the clinical features of the WD patients, efficacy and adverse effects of the drugs, and the experience of the physician. Liver transplantation is the only effective method to save patients with acute liver failure or with severe liver disease who fail drug treatment.     

Current and Near-Future Treatment of Alzheimer’s Disease

Recent findings have improved our understanding of the multifactorial nature of AD. While in early asymptomatic stages of AD, increased amyloid-β synthesis and tau hyperphosphorylation play a key role, while in the latter stages of the disease, numerous dysfunctions of homeostatic mechanisms in neurons, glial cells, and cerebrovascular endothelium determine the rate of progression of clinical symptoms. The main driving forces of advanced neurodegeneration include increased inflammatory reactions in neurons and glial cells, oxidative stress, deficiencies in neurotrophic growth and regenerative capacity of neurons, brain insulin resistance with disturbed metabolism in neurons, or reduction of the activity of the Wnt-β catenin pathway, which should integrate the homeostatic mechanisms of brain tissue. In order to more effectively inhibit the progress of neurodegeneration, combination therapies consisting of drugs that rectify several above-mentioned dysfunctions should be used. It should be noted that many widely-used drugs from various pharmacological groups, “in addition” to the main therapeutic indications, have a beneficial effect on neurodegeneration and may be introduced into clinical practice in combination therapy of AD. There is hope that complex treatment will effectively inhibit the progression of AD and turn it into a slowly progressing chronic disease. Moreover, as the mechanisms of bidirectional communication between the brain and microbiota are better understood, it is expected that these pathways will be harnessed to provide novel methods to enhance health and treat AD.     

Botulinum Toxin A Ameliorates Neuroinflammation in the MPTP and 6-OHDA-Induced Parkinson’s Disease Models

Recently, increasing evidence suggests that neuroinflammation may be a critical factor in the development of Parkinson’s disease (PD) in addition to the ratio of acetylcholine/dopamine because dopaminergic neurons are particularly vulnerable to inflammatory attack. In this study, we investigated whether botulinum neurotoxin A (BoNT-A) was effective for the treatment of PD through its anti-neuroinflammatory effects and the modulation of acetylcholine and dopamine release. We found that BoNT-A ameliorated MPTP and 6-OHDA-induced PD progression, reduced acetylcholine release, levels of IL-1β, IL-6 and TNF-α as well as GFAP expression, but enhanced dopamine release and tyrosine hydroxylase expression. These results indicated that BoNT-A had beneficial effects on MPTP or 6-OHDA-induced PD-like behavior impairments via its anti-neuroinflammation properties, recovering dopamine, and reducing acetylcholine release.     

Therapeutic Applications of Botulinum Neurotoxin for Autonomic Symptoms in Parkinson’s Disease: An Updated Review

Parkinson’s disease is the most common age-related motoric neurodegenerative disease. In addition to the cardinal motor symptoms of tremor, rigidity, bradykinesia, and postural instability, there are numerous non-motor symptoms as well. Among the non-motor symptoms, autonomic nervous system dysfunction is common. Autonomic symptoms associated with Parkinson’s disease include sialorrhea, hyperhidrosis, gastrointestinal dysfunction, and urinary dysfunction. Botulinum neurotoxin has been shown to potentially improve these autonomic symptoms. In this review, the varied uses of botulinum neurotoxin for autonomic dysfunction in Parkinson’s disease are discussed. This review also includes discussion of some additional indications for the use of botulinum neurotoxin in Parkinson’s disease, including pain.     

Neurodegenerative Pathways in Alzheimer’s Disease: A Review

Alzheimer’s disease (AD) is a complex neurodegenerative disease that leads to insidious deterioration of brain functions and is considered the sixth leading cause of death in the world. Alzheimer’s patients suffer from memory loss, cognitive deficit and behavioral changes; thus, they eventually follow a low-quality life. AD is considered as a multifactorial disorder involving different neuropathological mechanisms. Recent research has identified more than 20 pathological factors that are promoting disease progression. Three significant hypotheses are said to be the root cause of disease pathology, which include acetylcholine deficit, the formation of amyloid-beta senile plaques and tau protein hyperphosphorylation. Apart from these crucial factors, pathological factors such as apolipoprotein E (APOE), glycogen synthase kinase 3β, notch signaling pathway, Wnt signaling pathway, etc., are considered to play a role in the advancement of AD and therefore could be used as targets for drug discovery and development. As of today, there is no complete cure or effective disease altering therapies for AD. The current therapy is assuring only symptomatic relief from the disease, and progressive loss of efficacy for these symptomatic treatments warrants the discovery of newer drugs by exploring these novel drug targets. A comprehensive understanding of these therapeutic targets and their neuropathological role in AD is necessary to identify novel molecules for the treatment of AD rationally.     

Pyridopyrimidinone Derivatives as Potent and Selective c-Jun N-Terminal Kinase (JNK) Inhibitors

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Baicalein Attenuates Neuroinflammation by Inhibiting NLRP3/Caspase-1/GSDMD Pathway in MPTP-Induced Mice Model of Parkinson’s Disease

BackgroundInflammasome-induced neuroinflammation is a major pathogenic mechanism underlying the degeneration of nigral dopaminergic neurons in Parkinson’s disease (PD). Baicalein is a flavonoid isolated from the traditional Chinese medicinal herbal Scutellaria baicalensis Georgi with known anti-inflammatory and neuroprotective efficacy in models of neurodegenerative diseases, including PD. However, its effects on inflammasome-induced neuroinflammation during PD remain unclear.MethodsWe used N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD-like pathology in mice. Behavioral assessments including the pole test, rotarod test, and open field test were conducted to evaluate the effects of baicalein on MPTP-induced motor dysfunction. The efficacies of baicalein against MPTP-induced dopaminergic neuron loss and glial cell activation in the substantia nigra compact were examined by immunohistochemistry, effects on proinflammatory cytokines by quantitative real-time PCR and enzyme-linked immunosorbent assay, and effects on inflammasome pathway activation by immunoblotting and flow cytometry.ResultsAdministration of baicalein reversed MPTP-induced motor dysfunction, loss of dopaminergic neurons, and pro-inflammatory cytokine elevation. Baicalein also inhibited NLRP3 and caspase-1 activation and suppressed gasdermin D-dependent pyroptosis. Additionally, baicalein inhibited the activation and proliferation of disease-associated proinflammatory microglia.ConclusionsThese findings suggest that baicalein can reverse MPTP-induced neuroinflammation in mice by suppressing NLRP3/caspase-1/gasdermin D pathway. Our study provides potential insight into the use of baicalein in PD therapy.