Dysregulation of the leukotriene pathway in Parkinson's disease: The potential role of montelukast.

Parkinson's disease (PD) is a progressive neurodegenerative brain disease due to degeneration of dopaminergic neurons (DNs) presented with motor and non-motor symptoms. PD symptoms are developed in response to the disturbance of diverse neurotransmitters including γ-aminobutyric acid (GABA). GABA has a neuroprotective effect against PD neuropathology by protecting DNs in the substantia nigra pars compacta (SNpc). It has been shown that the degeneration of GABAergic neurons is linked with the degeneration of DNs and the progression of motor and non-motor PD symptoms. GABA neurotransmission is a necessary pathway for normal sleep patterns, thus deregulation of GABAergic neurotransmission in PD could be the potential cause of sleep disorders in PD. Sleep disorders affect GABA neurotransmission leading to memory and cognitive dysfunction in PD. For example, insomnia and short sleep duration are associated with a reduction of brain GABA levels. Moreover, PD-related disorders including rigidity and nocturia influence sleep patterns leading to fragmented sleep which may also affect PD neuropathology. However, the mechanistic role of GABA in PD neuropathology regarding motor and non-motor symptoms is not fully elucidated. Therefore, this narrative review aims to clarify the mechanistic role of GABA in PD neuropathology mainly in sleep disorders, and how good GABA improves PD. In addition, this review of published articles tries to elucidate how sleep disorders such as insomnia and REM sleep behavior disorder (RBD) affect PD neuropathology and severity. The present review has many limitations including the paucity of prospective studies and most findings are taken from observational and preclinical studies. GABA involvement in the pathogenesis of PD has been recently discussed by recent studies. Therefore, future prospective studies regarding the use of GABA agonists in the management of PD are suggested to observe their distinct effects on motor and non-motor symptoms. There is a bidirectional relationship between the pathogenesis of PD and sleep disorders which might be due to GABA deregulation.

Parkinson's disease (PD) is a common neurodegenerative disease developed due to the degeneration of dopaminergic neurons in the substantia nigra. There is no single effective treatment in the management of PD. Therefore, repurposing effective and approved drugs like metformin could be an effective strategy for managing PD. However, the mechanistic role of metformin in PD neuropathology was not fully elucidated. Metformin is an insulin-sensitizing agent used as a first-line therapy in the management of type 2 diabetes mellitus (T2DM) and has the ability to reduce insulin resistance (IR). Metformin may have a beneficial effect on PD neuropathology. The neuroprotective effect of metformin is mainly mediated by activating adenosine monophosphate protein kinase (AMPK), which reduces mitochondrial dysfunction, oxidative stress, and α-synuclein aggregation. As well, metformin mitigates brain IR a hallmark of PD and other neurodegenerative diseases. However, metformin may harm PD neuropathology by inducing hyperhomocysteinemia and deficiency of folate and B12. Therefore, this review aimed to find the potential role of metformin regarding its protective and detrimental effects on the pathogenesis of PD. The mechanistic role of metformin in PD neuropathology was not fully elucidated. Most studies regarding metformin and its effectiveness in PD neuropathology were observed in preclinical studies, which are not fully translated into clinical settings. In addition, metformin effect on PD neuropathology was previously clarified in T2DM, potentially linked to an increasing PD risk. These limitations hinder the conclusion concerning the therapeutic efficacy of metformin and its beneficial and detrimental role in PD. Therefore, as metformin does not cause hypoglycemia and is a safe drug, it should be evaluated in non-diabetic patients concerning PD risk.

Expression of enzymes and receptors of leukotriene pathway genes in equine endometrium during the estrous cycle and early pregnancy

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive motor and non-motor symptoms. PD neuropathology is due to the progressive deposition of mutant alpha-synuclein (α-Syn) in the dopaminergic neurons of the substantia nigra pars compacta (SNpc). This effect initiates oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis of the dopaminergic neurons in the SNpc. PD neuropathology, which is closely associated with inflammatory and oxidative disorders, disrupts different vital cellular pathways. Notably, the current anti-PD medications only relieve the symptoms of PD without averting the underlying neuropathology. Thus, it is advisable to search for novel drugs that attenuate the progression of PD neuropathology. It has been shown that phosphatidylinositol 3-kinase (PI3K), AKT, and glycogen synthase kinase 3 beta (GSK3β) signaling pathways are affected in PD. PI3K/AKT pathway is neuroprotective against the development and progression of PD. However, the over-activated GSK3β signaling pathway has a detrimental effect on PD neuropathology by inducing inflammation and oxidative stress. Dysregulation of the PI3K/AKT/GSK3β signaling pathway provokes brain insulin resistance (BIR), neuroinflammation, and neuronal apoptosis, the hallmarks of PD and other neurodegenerative diseases. However, the mechanistic role of the PI3K/AKT/GSK3β signaling pathway is not fully clarified. Therefore, in this review, we intend to discuss the role of the PI3K/AKT/GSK3β signaling pathway in PD pathogenesis and how PI3K/AKT activators and GSK3β inhibitors have helped effectively manage PD.

Previous studies have shown that the allergic late airway response (LR) is dependent on the leukotriene (LT) pathway in Brown Norway (BN) rats. In this same model, interleukin-2 (IL-2) has been shown to increase allergic airway responses without increasing LT production. This study examined the relationship between the upregulation of cellular immunity with IL-2 and the LT pathway in ovalbumin-sensitized BN rats. Airway responsiveness to LTD(4) was significantly increased in BN rats pretreated with IL-2 (20,000 U twice a day for 4.5 days). Treatment with montelukast, a cysteinyl LT(1) receptor antagonist, blocked IL-2's induced increase of the LR to ovalbumin challenge. When cytokine expression was assessed either by semiquantitative polymerase chain reaction or in situ hybridization, we found that montelukast decreased the amount of IL-4 mRNA expression in the lungs while increasing the amount of interferon-gamma mRNA expression 8 hours after challenge. These results indicate that upregulation of cellular immunity with IL-2 can increase the sensitivity of the airways to LTD(4) and that inhibition of the LT pathway will block the LR and modulate cytokine expression after antigen challenge.

Parkinson disease (PD) is one of the most common neurodegenerative diseases of the brain. Of note, brain renin-angiotensin system (RAS) is intricate in the PD neuropathology through modulation of oxidative stress, mitochondrial dysfunction and neuroinflammation. Therefore, modulation of brain RAS by angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) may be effective in reducing the risk and PD neuropathology. It has been shown that all components including the peptides and enzymes of the RAS are present in the different brain areas. Brain RAS plays a critical role in the regulation of memory and cognitive function, and in the controlling of central blood pressure. However, exaggerated brain RAS is implicated in the pathogenesis of different neurodegenerative diseases including PD. Two well-known pathways of brain RAS are recognized including; the classical pathway which is mainly mediated by AngII/AT1R has detrimental effects. Conversely, the non-classical pathway which is mostly mediated by ACE2/Ang1-7/MASR and AngII/AT2R has beneficial effects against PD neuropathology. Exaggerated brain RAS affects the viability of dopaminergic neurons. However, the fundamental mechanism of brain RAS in PD neuropathology was not fully elucidated. Consequently, the purpose of this review is to disclose the mechanistic role of RAS in in the pathogenesis of PD. In addition, we try to revise how the ACEIs and ARBs can be developed for therapeutics in PD.

Background: Fevipiprant is a selective prostaglandin D2 receptor 2 (DP2) receptor antagonist which reduces eosinophilic airway inflammation in patients with persistent asthma and elevated sputum eosinophil counts. CD4+Th2 cells are a source of type 2 cytokines in asthma, via DP2 and leukotriene (LT) pathway activation. Aim: To compare fevipiprant with montelukast for suppression of type 2 cytokine and other inflammatory mediator production from human Th2 cells in the presence of endogenous stimuli of DP2 and LT pathways from activated mast cell (MC) supernatants. Methods: CD4+ T cells were isolated from healthy volunteers (HV), differentiated with IL-2/IL-4, sorted for DP2 expression and stimulated with MC supernatants in presence or absence of fevipiprant (1 µM) or montelukast (1 µM). mRNA was isolated and RT-PCR conducted on cytokines. MCs were CD34+ precursor cells from HV, differentiated and stimulated with IgE/anti-IgE in the presence or absence of cPLA2 inhibitor ZPL521 (20 µM) as positive control. Results: MC supernatants induced substantial activation of human DP2+ Th2 cells as suggested by increases in mRNA expression of IL-5 and IL-13. These increases were fully suppressed by fevipiprant, but not by montelukast, which only gave partial (~ 40%) reduction of IL-5 and IL-13 expression. Similar differences between drugs were found for suppression of increases in IL-3, IL-4, IL-8, M-CSF and GM-CSF mRNA expression. Conclusion: Consistent with the greater amplitude of inflammation induced by the DP2 pathway compared to the LT pathway, fevipiprant is superior to montelukast in suppressing type 2 and other inflammatory cytokine production in human MC-stimulated Th2 cells.

Despite advances in treatment, asthma continues to be a significant health and economic burden. Although asthma cannot be cured, several drugs, including beta2 agonists, corticosteroids, and leukotriene (LT) modifiers, are well tolerated and effective in minimizing symptoms, improving lung function, and preventing exacerbations. However, inter-patient variability in response to asthma drugs limits their effectiveness. It has been estimated that 60-80% of this inter-patient variability may be attributable to genetic variation. LT modifiers, in particular, have been associated with heterogeneity in response. These drugs exert their action by inhibiting the activity of cysteinyl leukotrienes (CysLTs), which are potent bronchoconstrictors and pro-inflammatory agents. Two classes of LT modifiers are 5-lipoxygenase (ALOX5) inhibitors (zileuton) and leukotriene receptor antagonists (LTRAs) [montelukast, pranlukast, and zarfirlukast]. LT modifiers can be used as alternatives to low-dose inhaled corticosteroids (ICS) in mild persistent asthma, as add-on therapy to low- to medium-dose ICS in moderate persistent asthma, and as add-on to high-dose ICS and a long-acting ss2 agonist in severe persistent asthma. At least six genes encode key proteins in the LT pathway: arachidonate 5-lipoxygenase (ALOX5), ALOX5 activating protein (ALOX5AP [FLAP]), leukotriene A4 hydrolase (LTA4H), LTC4 synthase (LTC4S), the ATP-binding cassette family member ABCC1 (multidrug resistance protein 1 [MRP1]), and cysteinyl leukotriene receptor 1 (CYSLTR1). Studies have reported that genetic variation in ALOX5, LTA4H, LTC4S, and ABCC1 influences response to LT modifiers. Plasma concentrations of LTRAs vary considerably among patients. Physio-chemical characteristics make it likely that membrane efflux and uptake transporters mediate the absorption of LTRAs into the systemic circulation following oral administration. Genes that encode efflux and uptake transport proteins harbor many variants that could influence the pharmacokinetics, and particularly the bioavailability, of LTRAs, and could contribute to heterogeneity in response. In the future, large, well designed clinical trials studying the pharmacogenetics of LT modifiers in diverse populations are warranted to determine whether a genetic signature can be developed that will accurately predict which patients will respond.

ABSTRACTIntroduction: Asthma is a chronic inflammatory disease of the airways with a large heterogeneity of clinical phenotypes. There has been increasing interest regarding the role of cysteinyl leukotriene (LT) and leukotriene receptor antagonists (LTRA) in asthma treatment.Areas covered: This review summarized the data (published in PubMed during 1984–2019) regarding LTRA treatment in asthma and LTs-related airway inflammation mechanisms. Involvement of LTs C4/D4/E4 has been demonstrated in the several aspects of airway inflammation and remodeling. Novel pathways related to LTE4, the most potent mediator, and its respective receptors have recently been studied. Antagonists against cysteinyl leukotriene receptor (CysLTR) type 1, including montelukast, pranlukast and zafirlukast, have been widely prescribed in clinical practices; however, some clinical trials have shown insignificant responses to LTRAs in adult asthmatics, while some phenotypes of adult asthma showed more favorable responses to LTRAs including aspirin-exacerbated respiratory disease, elderly asthma, asthma associated with smoking, obesity and allergic rhinitis.Expert opinion: Further investigations are needed to understand the role of LTs in airway inflammation and remodeling of the asthmatic airways. There is a lack of biomarkers to predict responsiveness to LTRA, especially in adult asthmatics. Besides CysLTR1 antagonists, targets aiming other LT pathways should be considered.

Anti-leukotrienes: the promise for asthma?: Novel Inhibitors of Leukotrienes [Series: Progress in Inflammation Research (edited by Michael J. Parnham)] edited by G. Folco, B. Samuelsson and R.C. Murphy

Parkinson's disease (PD) is a progressive neurodegenerative disease of the brain due to degeneration of dopaminergic neurons in the substantia nigra (SN). Glycogen synthase kinase 3 beta (GSK-3β) is implicated in the pathogenesis of PD. Therefore, the purpose of the present review was to revise the mechanistic role of GSK-3β in PD neuropathology, and how GSK-3β inhibitors affect PD neuropathology. GSK-3 is a conserved threonine/serine kinase protein that is intricate in the regulation of cellular anabolic and catabolic pathways by modulating glycogen synthase. Over-expression of GSK-3β is also interconnected with the development of different neurodegenerative diseases. However, the underlying mechanism of GSK-3β in PD neuropathology is not fully clarified. Over-expression of GSK-3β induces the development of PD by triggering mitochondrial dysfunction and oxidative stress in the dopaminergic neurons of the SN. NF-κB and NLRP3 inflammasome are activated in response to dysregulated GSK-3β in PD leading to progressive neuronal injury. Higher expression of GSK-3β in the early stages of PD neuropathology might contribute to the reduction of neuroprotective brain-derived neurotrophic factor (BDNF). Thus, GSK-3β inhibitors may be effective in PD by reducing inflammatory and oxidative stress disorders which are associated with degeneration of dopaminergic in the SN.

LRP1 at the crossroads of Parkinson's and Alzheimer's: Divergent roles in α-synuclein and amyloid pathology.

Parkinson's disease (PD) is the second most frequent neurodegenerative brain disease (NBD) after Alzheimer's disease (AD). Statins are the most common lipid‐lowering agents used in the management of dyslipidemia and the prevention of primary and secondary cardiovascular diseases (CVD) events. In addition, there is a controversial point regarding the role of serum lipids in the pathogenesis of PD. In this bargain, as statins reduce serum cholesterol so they affect the PD neuropathology in bidirectional ways either protective or harmful. Statins are not used in the management of PD, but they are frequently used in the cardiovascular disorders commonly associated with PD in the elderly population. Therefore, the use of statins in that population may affect PD outcomes. Concerning the potential role of statins on PD neuropathology, there are conflicts and controversies either protective against the development of PD or harmful by increasing the risk for the development of PD. Therefore, this review aimed to clarify the precise role of statins in PD regarding the pros and cons from published studies. Many studies suggest a protective role of statins against PD risk through the modulation of inflammatory and lysosomal signaling pathways. Nevertheless, other observations suggest that statin therapy may increase PD risk by diverse mechanisms including reduction of CoQ10. In conclusion, there are strong controversies regarding the protective role of statins in PD neuropathology. Therefore, retrospective and prospective studies are necessary in this regard.

The conceivable role of prolactin hormone in Parkinson disease: The same goal but with different ways.

Acute coronary syndrome (ACS) is a set of signs and symptoms caused by a reduction of coronary blood flow with subsequent myocardial ischemia. ACS is associated with activation of the leukotriene (LT) pathway with subsequent releases of various LTs, including LTB4, LTC4, and LTD4, which cause inflammatory changes and induction of immunothrombosis. LTs through cysteine leukotriene (CysLT) induce activation of platelets and clotting factors with succeeding coronary thrombosis. CysLT receptor (CysLTR) antagonists such as montelukast (MK) may reduce the risk of the development of ACS and associated complications through suppression of the activation of platelet and clotting factors. Thus, this critical review aimed to elucidate the possible protective role of MK in the management of ACS. The LT pathway is implicated in the pathogenesis of atherosclerosis, cardiac hypertrophy, and heart failure. Inhibition of the LT pathway and CysL1TR by MK might be effective in preventing cardiovascular complications. MK could be an effective novel therapy in the management of ACS through inhibition of pro-inflammatory CysLT1R and modulation of inflammatory signaling pathways. MK can attenuate thrombotic events by inhibiting platelet activation and clotting factors that are activated during the development of ACS. In conclusion, MK could be an effective agent in reducing the severity of ACS and associated complications. Experimental, preclinical, and clinical studies are recommended to confirm the potential therapeutic of MK in the management of ACS.