Non-steroidal anti-inflammatory drugs in Parkinson's disease

Parkinson's disease (PD) is known to be a chronic and progressive neurodegenerative disease caused by a selective degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). A large body of experimental evidence indicates that the factors involved in the pathogenesis of this disease are several, occurring inside and outside the DAergic neuron. Recently, the role of the neuron-glia interaction and the inflammatory process, in particular, has been the object of intense study by the research community. It seems to represent a new therapeutic approach opportunity for this neurological disorder. Indeed, it has been demonstrated that the cyclooxygenase type 2 (COX-2) is up-regulated in SNc DAergic neurons in both PD patients and animal models of PD and, furthermore, non-steroidal anti-inflammatory drugs (NSAIDs) pre-treatment protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6 hydroxydopamine (6-OHDA)-induced nigro-striatal dopamine degeneration. Moreover, recent epidemiological studies have revealed that the risk of developing PD is reduced in humans who make therapeutical use of NSAIDs. Consequently, it is hypothesized that they might delay or prevent the onset of PD. However, whether or not these common drugs may also be of benefit to those individuals who already have Parkinson's disease has not as yet been shown. In this paper, evidence relating to the protective effects of aspirin or other NSAIDs on DAergic neurons in animal models of Parkinson's disease will be discussed. In addition, the pharmacological mechanisms by which these molecules can exert their neuroprotective effects will be reviewed. Finally, epidemiological data exploring the effectiveness of NSAIDs in the prevention of PD and their possible use as adjuvants in the therapy of this neurodegenerative disease will also be examined.     

Non-steroidal anti-inflammatory drug (NSAID) use and Alzheimer disease in community-dwelling elderly patients.

OBJECTIVE: Recently, greater attention has been paid to the role of inflammatory processes in the pathophysiology of Alzheimer disease (AD). However, the mechanism by which anti-inflammatory agents (NSAIDs) might slow the progression of AD is not completely known. The aim of the present study was to examine the relationship between NSAIDs use and AD in a large sample of community-dwelling elderly people. METHODS: In a cross-sectional retrospective study, the authors analyzed data on patients admitted to home care programs. A total of 12 home health agencies participated in the project, with a total of 2,708 patients enrolled in the present study. The main outcome measures were the prevalence of AD and use of NSAIDs treatment. RESULTS: Compared with all non-users, NSAID users had a nearly 50% lower risk of being affected by AD. Separate multivariate analyses of subjects receiving different types of NSAIDs found a significantly decreased risk of cognitive impairment associated with non-aspirin NSAID use, whereas, among subjects taking aspirin, the difference in estimated risk did not reach statistical significance. CONCLUSION: The results of this population-based cross-sectional study are consistent with the notion that long-term NSAIDs use has a protective effect against AD. However, after possible confounding effects of age and several other variables potentially associated with cognitive impairment were controlled, this association was statistically significant only for non-aspirin NSAIDs use.     

Non-steroidal anti-inflammatory drug use and the risk of Parkinson disease: a retrospective cohort study.

Using the British Columbia Linked Health Databases, we explored the association between nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of developing Parkinson's disease (PD). We followed a cohort of older adults in the Province of British Columbia from 1997 to 2003. A time-dependent Cox model was used to estimate adjusted rate ratios for users and non-users of NSAIDs. The results of our study did not show a protective effect of NSAIDs for PD (rate ratio 0.84, 95% CI 0.81-1.09).     

Partial inhibition of proteasome activity enhances remyelination after cuprizone-induced demyelination

We have previously demonstrated that addition of low concentrations of lactacystin (a specific inhibitor of the proteasome) to oligodendroglial cell cultures containing a high percentage of precursor cells induces their exit from the cell cycle and their differentiation. On the other hand, we have recently shown that the mechanism of cuprizone toxicity on oligodendroglial cells involves the recruitment of microglia and their secretion of pro-inflammatory cytokines and in the increased production of oxidant species, which results in a decrease in the activities of the mitochondrial respiratory chain. In the present paper we investigated the effect of a decrease in proteasome activity induced by the injection of lactacystin in the corpus callosum in the remyelination process that normally occurs after cuprizone-induced demyelination. This treatment markedly improves the remyelination process that normally occurs in cuprizone-induced demyelination. It also attenuates the activation of NFκB and the recruitment of microglia and astrocytes, thus helping in the recovery of the mitochondrial respiratory chain activities that are affected by cuprizone treatment.     

Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents in the treatment of neurodegenerative disease

Inflammation is characteristic of a broad spectrum of neurodegenerative diseases. These include Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases, amyotrophic lateral sclerosis, all of the tauopathies, multiple sclerosis and many other less common conditions. Morphologically, the level of inflammation is determined by the concentration and degree of activation of microglial cells. Biochemically, it is judged by the presence of a spectrum of inflammatory mediators. Epidemiological evidence indicates that anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs) have a sparing effect on AD and PD indicating that inflammation exacerbates the pathology in these diseases. NSAIDs are protective in transgenic animal models of AD, providing further evidence of the negative consequences of inflammation. Here we describe an in vitro model, which was used to study the protective effects of NSAIDs in AD. This model is based on neuronal cell killing by stimulated microglia or microglia-like cells. In this model NSAIDs show protective effects at a therapeutically relevant level, which is in the low micromolar range. There are reports suggesting that NSAIDs act independently of cyclooxygenase (COX) inhibition, but only at higher doses. Classical NSAIDs are still the most logical choice for agents that will slow the progression or delay the onset of AD and other neurodegenerative diseases despite failures of naproxen, celecoxib and rofecoxib in AD clinical trials. Several other classes of anti-inflammatory drugs have been identified as potentially beneficial in this and similar assay systems. Therefore combination therapy with other anti-inflammatory agents that work through different mechanisms of action might prove to be a superior therapeutic strategy.     

The endocannabinoid 2-AG enhances spontaneous remyelination by targeting microglia

Remyelination is an endogenous process by which functional recovery of damaged neurons is achieved by reinstating the myelin sheath around axons. Remyelination has been documented in multiple sclerosis (MS) lesions and experimental models, although it is often incomplete or fails to affect the integrity of the axon, thereby leading to progressive disability. Microglia play a crucial role in the clearance of the myelin debris produced by demyelination and in inflammation-dependent OPC activation, two processes necessary for remyelination to occur. We show here that following corpus callosum demyelination in the TMEV-IDD viral murine model of MS, there is spontaneous and partial remyelination that involves a temporal discordance between OPC mobilization and microglia activation. Pharmacological treatment with the endocannabinoid 2-AG enhances the clearance of myelin debris by microglia and OPC differentiation, resulting in complete remyelination and a thickening of the myelin sheath. These results highlight the importance of targeting microglia during the repair processes in order to enhance remyelination.     

Combination therapy of apo‐transferrin and thyroid hormones enhances remyelination

The current study presents two different approaches with a view to elucidating the interaction between thyroid hormones (TH) and apo‐transferrin (aTf) and their role in myelination and remyelination. First, in vitro assays were conducted to determine the single and combined effects of aTf and triiodothyronine (T3) on oligodendroglial cell lineage proliferation and oligodendrocyte (OLG) maturation in primary cultures. Results revealed higher proliferation rates upon single aTf treatment but Control values upon T3 and aTf + T3 treatments. In addition, both aTf and T3 accelerated OLG maturation, with the greatest effects being exerted by combined aTf + T3 administration in terms of both myelin basic protein (MBP) expression and morphological complexity. Second, in vivo assays were carried out to establish single and combined effects of aTf and T3, as well as TH receptor (THR) inhibitor I‐850, on remyelination following a CPZ‐induced demyelination protocol. Results showed an increase in myelin deposition and the number of mature remyelinating OLG upon single treatments, but a synergic effect upon combined aTf + T3 treatment which was prevented by THR inhibition. It may be thus concluded that combined treatment yielded the most beneficial effects on OLG maturation parameters in vitro and remyelinating capacity in vivo when compared to single treatments. These findings may help explore the development of new target molecules in the treatment of demyelinating diseases.     

Non-steroidal anti-inflammatory drug sodium salicylate,but not diclofenac or celecoxib,protects against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats

We evaluated the hydroxyl radical (*OH) scavenging action of nonsteroidal anti-inflammatory drugs (NSAIDs), sodium salicylate (SA), diclofenac and celecoxib in Fenton's reaction and their neuroprotective effects in 1-methyl-4-phenylpyridinium (MPP(+))-induced striatal dopamine (DA) depletion in rats. Salicylate hydroxylation procedure employing HPLC-electrochemistry was used to assay formation of *OH in Fenton's reaction in test tubes. While SA dose- and time-dependently hydroxylated itself and inactivated *OH, celecoxib (up to 10 mM) showed no effect on *OH formation and diclofenac caused a reduction in *OH generation only at high doses (100 microM-10 mM). Administration of the non-selective cyclooxygenase (COX) inhibitor, SA (50, 100 mg/kg, i.p.) significantly attenuated striatal DA depletion caused by intrastriatal infusion of MPP(+) (100 nmol in 4 microl). Treatment with another nonselective, reversible COX inhibitor, diclofenac (5, 10 mg/kg) did not protect against MPP(+)-induced DA depletion. The selective COX-2 inhibitor, celecoxib (2.5-50 mg/kg) treatment exacerbated MPP(+)-induced decrease in DA. Failure of celecoxib or diclofenac to render protection in animals against MPP(+)-induced DA depletion indicates absence of prostaglandin involvement in MPP(+) action. These results also suggest that the neuroprotective ability of SA is independent of prostaglandin mediation. A relationship between inactivation of *OH by SA and its ability to protect DA depletion in the striatum caused by MPP(+) indicates a direct involvement of *OH in the action of this neurotoxin. The present study establishes potent neuroprotective activity of SA and suggests the use of aspirin in adjuvant therapy in Parkinson's disease.     

Promoting remyelination in multiple sclerosis by endogenous adult neural stem/precursor cells

Although the treatment of multiple sclerosis has made significant strides in the last decade, successful translation from laboratory to clinical medicine of neuronal repair remains a therapeutic challenge. Nevertheless, advances in the biology of stem and precursor cells, particularly in relation to myelin damage, make this a realistic proposition during the next decade. Replacing lost myelin (remyelination) is currently thought to be an important clinical objective because of the role it might play in slowing or preventing axonal degeneration. Stem/precursor cell-based strategies for enhancing remyelination can be divided into those in which cell are transplanted into a patients (exogenous or cell therapies) and those in which the patients own stem/precursor cells are mobilised to more efficiently engage in healing areas of demyelination (endogenous or pharmacological therapies). While the two approaches tend to be regarded separately they are not mutually exclusive. This article focuses on the endogenous approach and reviews the nature and nomenclature of the stem and precursor cells present within the adult CNS that engage in remyelination and that are therefore potential targets for pharmacological manipulation.     

Exogenous leukemia inhibitory factor stimulates oligodendrocyte progenitor cell proliferation and enhances hippocampal remyelination

New CNS neurons and glia are generated throughout adulthood from endogenous neural stem and progenitor cells. These progenitors can respond to injury, but their ability to proliferate, migrate, differentiate, and survive is usually insufficient to replace lost cells and restore normal function. Potentiating the progenitor response with exogenous factors is an attractive strategy for the treatment of nervous system injuries and neurodegenerative and demyelinating disorders. Previously, we reported that delivery of leukemia inhibitory factor (LIF) to the CNS stimulates the self-renewal of neural stem cells and the proliferation of parenchymal glial progenitors. Here we identify these parenchymal glia as oligodendrocyte (OL) progenitor cells (OPCs) and show that LIF delivery stimulates their proliferation through the activation of gp130 receptor signaling within these cells. Importantly, this effect of LIF on OPC proliferation can be harnessed to enhance the generation of OLs that express myelin proteins and reform nodes of Ranvier in the context of chronic demyelination in the adult mouse hippocampus. Our findings, considered together with the known beneficial effects of LIF on OL and neuron survival, suggest that LIF has both reparative and protective activities that make it a promising potential therapy for CNS demyelinating disorders and injuries.     

Clemastine rescues behavioral changes and enhances remyelination in the cuprizone mouse model of demyelination

Increasing evidence suggests that white matter disorders based on myelin sheath impairment may underlie the neuropathological changes in schizophrenia.But it is unknown whether enhancing remyelination is a beneficial approach to schizophrenia.To investigate this hypothesis,we used clemastine,an FDA-approved drug with high potency in promoting oligodendroglial differentiation and myelination,on a cuprizone-induced mouse model of demyelination.The mice exposed to cuprizone(0.2%in chow) for 6 weeks displayed schizophrenia-like behavioral changes,including decreased exploration of the center in the open field test and increased entries into the arms of the Y-maze,as well as evident demyelination in the cortex and corpus callosum.Clemastine treatment was initiated upon cuprizone withdrawal at 10 mg/kg per day for3 weeks.As expected,myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes(APC-positive) and myelin basic protein.More importantly,the clemastine treatment rescued the schizophrenia-like behavioral changes in the open field test and the Y-maze compared to vehicle,suggesting a beneficial effect via promoting myelin repair.Our findings indicate that enhancing remyelination may be a potential therapy for schizophrenia.     

Non-steroidal anti-inflammatory drugs(NSAIDs) and neuroprotection in the elderly a view from the mitochondria

<正>The most important risk factor for stroke and neurodegeneration is aging.In fact,survival after stroke diminishes largely with aging.In fact,recovery after brain artery occlusion is dramatically worsened by aging,even normal aging is associated with neuron damage and cognitive decline.Mechanisms involved in aging-related,cognitive decline and susceptibility to neuron damage in stroke and neurodegeneration are largely unknown.One of the most important     

Osteopontin is upregulated during in vivo demyelination and remyelination and enhances myelin formation in vitro

We have used in vitro oligodendrocyte differentiation and the in vivo remyelination model, the cuprizone model, to identify genes regulating oligodendrocyte function and remyelination. One of the genes we identified, osteopontin (opn), is a secreted glycoprotein with cytokine-like, chemotactic, and anti-apoptotic properties that contains an Arg-Gly-Asp (RGD) cell adhesion motif-mediating interactions with several integrins. Both microglia and astrocytes in demyelinating brain regions of cuprizone-fed mice expressed OPN protein. Recombinant OPN protein produced in a baculovirus expression system induced proliferation of both the rat CG-4 and the mouse Oli-neu oligodendrocyte precursor (OLP)-like cell lines in a dose-dependent manner. In addition, recombinant OPN treatment stimulated both myelin basic protein (MBP) synthesis and myelin sheath formation in mixed cortical cultures from embryonic mouse brain, an in vitro primary culture model of myelination. Interestingly, myelinating mixed cultures prepared from OPN(-/-) mice contained significantly less MBP compared to wild-type cultures after 17 days in culture. We propose that in the central nervous system, OPN may act as a novel regulator of myelination and remyelination.     

CXCR4 signaling regulates remyelination by endogenous oligodendrocyte progenitor cells in a viral model of demyelination

Following intracranial infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV), susceptible mice will develop widespread myelin destruction that results in pathological and clinical outcomes similar to those seen in humans with the demyelinating disease Multiple Sclerosis (MS). Partial remyelination and clinical recovery occurs during the chronic phase following control of viral replication yet the signaling mechanisms regulating these events remain enigmatic. Here we report the kinetics of proliferation and maturation of oligodendrocyte progenitor cells (OPCs) within the spinal cord following JHMV-induced demyelination and that CXCR4 signaling contributes to the maturation state of OPCs. Following treatment with AMD3100, a specific inhibitor of CXCR4, mice recovering from widespread demyelination exhibit a significant (P < 0.01) increase in the number of OPCs and fewer (P < 0.05) mature oligodendrocytes compared with HBSS-treated animals. These results suggest that CXCR4 signaling is required for OPCs to mature and contribute to remyelination in response to JHMV-induced demyelination. To assess if this effect is reversible and has potential therapeutic benefit, we pulsed mice with AMD3100 and then allowed them to recover. This treatment strategy resulted in increased numbers of mature oligodendrocytes, enhanced remyelination, and improved clinical outcome. These findings highlight the possibility to manipulate OPCs in order to increase the pool of remyelination-competent cells that can participate in recovery.     

Promoting remyelination in multiple sclerosis by endogenous adult neural stem/precursor cells: defining cellular targets

Although the treatment of multiple sclerosis has made significant strides in the last decade, the therapeutic enhancement of repair has yet to make the successful translation from laboratory to clinic. Nevertheless, advances in the biology of stem and precursor cells, particularly in relation to myelin damage, make this a realistic proposition during the next decade. Replacing lost myelin (remyelination) is currently thought to be an important clinical objective because of the role it might play in slowing or preventing axonal degeneration. Stem/precursor cell-based strategies for enhancing remyelination can be divided into those in which cells are transplanted into a patient (exogenous or cell therapies) and those in which the patient's own stem/precursor cells are mobilised to more efficiently engage in healing areas of demyelination (endogenous or pharmacological therapies). While the two approaches tend to be regarded separately they are not mutually exclusive. This article focuses on the endogenous approach and reviews the nature and nomenclature of the stem and precursor cells present within the adult CNS that engage in remyelination and that are therefore potential targets for pharmacological manipulation.     

Salsolinol, an endogenous neurotoxin, enhances platelet aggregation and thrombus formation

Salsolinol, an endogenous neurotoxin, is known to be involved in the neuropathy of Parkinson's disease and chronic alcoholism. In these diseases, increased thrombotic events are also commonly reported, yet the mechanism underlying remains poorly understood. Here we report that salsolinol can enhance agonist-induced platelet aggregation and granular secretion, which is essential in the thrombus formation. In rat and human platelets, agonist-induced platelet aggregation was significantly increased by salsolinol in a concentration-dependent manner. Agonist-induced granular secretions of serotonin and concomitant P-selectin expression were also augmented by salsolinol. alpha2-adrenergic blockers attenuated the salsolinol-enhanced aggregation and the inhibition of cyclic AMP generation was found, suggesting the involvement of alpha2-adrenergic receptor-mediated pathways in these events. In accord with the in-vitro results, in an arterial and venous thrombosis model in vivo in the rat, salsolinol shortened vessel occlusion time and increased thrombus formation, respectively. In conclusion, we demonstrated that salsolinol can enhance agonist-induced aggregation and granular secretion in platelets through alpha2-adrenergic receptor activation, which resulted in the increased thrombus formation in vivo. These results suggest that salsolinol-enhanced platelet aggregation could be a possible contributing factor to the thrombotic events observed in Parkinson's disease and alcoholism.