Neuroprotective effects of boron nitride nanoparticles in the experimental Parkinson’s disease model against MPP+ induced apoptosis

Metabolic Brain Disease - Parkinson’s disease (PD) is one of the most aggressive neurodegenerative diseases and characterized by the loss of dopamine-sensitive neurons in the substantia nigra...     

The risk of Parkinson’s disease in type 1 Gaucher disease

In Gaucher disease, defective lysosomal glucocerebrosidase due to mutations in the GBA1 gene results in lysosomal accumulation of glucocerebroside in mononuclear phagocytes and a multisystemic phenotype. Observations of occurrence of Parkinson’s disease in some patients with non-neuronopathic type 1 Gaucher disease (GD1) and their first degree relatives has led to the identification of GBA1 heterozygous mutations as a genetic risk factor for idiopathic Parkinson’s disease (PD). However, the magnitude of risk of PD in patients with known GD1 has not been determined, and it is not known whether GD1/PD represents a specific sub-phenotype of GD1 with distinctive genotype/phenotype characteristics. We estimated the risk of PD in a cohort of 444 consecutively evaluated patients with GD1 compared to that in the general population. Eleven patients developed parkinsonian syndrome during a 12-year follow-up period. The adjusted life-time risk ratio of PD in GD1 compared to that in the general population was 21.4 [95% confidence interval (95% CI) 10.7–38.3], with a higher risk in men compared to women. In our cohort, GD1/Parkinson’s disease phenotype (GD1/PD) was characterized by higher GD1 severity score, due to higher incidence of avascular osteonecrosis. The clinical spectrum of PD varied from mild to potentially life-threatening disease. All but one patient with GD1/PD phenotype had at least one N370S GBA1 allele. In conclusion, compared to the general population, patients with GD1 have an almost 20-fold increased life-time risk of developing PD.     

Targeting β-arrestin2 in the treatment of l-DOPA–induced dyskinesia in Parkinson’s disease

Parkinson’s disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursor l-3,4-dihydroxyphenylalanine (l-DOPA), but its prolonged use causes dyskinesias referred to as l-DOPA–induced dyskinesias (LIDs). Recent studies in animal models of PD have suggested that dyskinesias are associated with the overactivation of G protein-mediated signaling through DA receptors. β-Arrestins desensitize G protein signaling at DA receptors (D1R and D2R) in addition to activating their own G protein-independent signaling events, which have been shown to mediate locomotion. Therefore, targeting β-arrestins in PD l-DOPA therapy might prove to be a desirable approach. Here we show in a bilateral DA-depletion mouse model of Parkinson’s symptoms that genetic deletion of β-arrestin2 significantly limits the beneficial locomotor effects while markedly enhancing the dyskinesia-like effects of acute or chronic l-DOPA treatment. Viral rescue or overexpression of β-arrestin2 in knockout or control mice either reverses or protects against LIDs and its key biochemical markers. In other more conventional animal models of DA neuron loss and PD, such as 6-hydroxydopamine–treated mice or rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine–treated nonhuman primates, β-arrestin2 overexpression significantly reduced dyskinesias while maintaining the therapeutic effect of l-DOPA. Considerable efforts are being spent in the pharmaceutical industry to identify therapeutic approaches to block LIDs in patients with PD. Our results point to a potential therapeutic approach, whereby development of either a genetic or pharmacological intervention to enhance β-arrestin2- or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy.Dopamine (DA) is a major catecholamine neurotransmitter that is released by midbrain DA neurons. DA activates G protein-coupled receptors (GPCRs), which belong to the dopamine D1 (D1R and D5R) or D2 (D2R, D3R, and D4R) class of DA receptors that are known to signal via G protein-dependent mechanisms (1, 2). However, recent studies have shown that in addition to G protein-mediated signaling, many GPCRs, including DA receptors, signal through beta-arrestin 1 and 2 (βarr1 and βarr2)-dependent mechanisms (3, 4). The two isoforms of β-arrestin, β-arrestin1 (βarr1) and β-arrestin2 (βarr2) are widely coexpressed in the brain (5, 6). β-Arrestins were originally appreciated for their ability to desensitize (i.e., turn off) GPCR signaling in a GPCR kinase (GRK)-dependent manner (7, 8). Binding of β-arrestin to the GPCR sterically hinders G protein binding and in most instances initiates receptor endocytosis via interactions with adaptor protein complex-2 (AP-2) and clathrin (9–11). It is now appreciated that β-arrestins regulate physiology and behaviors independently of G protein signaling through their ability to scaffold multiple intracellular signaling molecules such as kinases and phosphatases (3, 4, 12, 13). Studies from our laboratory have shown that through both dopamine D1 and D2 receptors, βarr2-mediated signaling plays a major role in DA-dependent locomotion (14–16).Parkinson’s disease (PD) is a neurodegenerative disorder caused by the progressive loss of DA neurons projecting to the striatum that is characterized by severe locomotor deficits and is commonly treated with the DA precursor l-3,4-dihydroxyphenylalanine (l-DOPA) or D2 receptor agonists. Although l-DOPA treatment ameliorates the locomotor deficits, prolonged l-DOPA use causes dyskinesias, termed as l-DOPA–induced dyskinesias (LIDs) in humans or abnormal involuntary movements (AIMs) in animal models. Despite these drawbacks, l-DOPA is still the mainstay of PD treatment for its unsurpassed antiparkinsonian efficacy. Studies in animal models of PD suggest that dyskinesias are associated with enhanced G protein-mediated signaling at dopamine receptors (17–23) potentially leading to changes in gene expression and uncontrolled neuronal excitability (21, 24–28). Therefore, PD therapy strategies that moderate G protein signaling and neuronal excitability while maintaining normal movement may be an ideal way to eliminate DA receptor-associated dyskinesias. To moderate this uncontrolled signaling or neuronal excitability, several approaches have been explored such as reducing D1R surface expression (29, 30), dampening overactive intracellular signaling (20, 23, 31, 32), and inhibiting A2A (33, 34), mGluR5 (35–37) or NMDA receptors (24, 25, 38–40). Although these targets have clinical potential, several drugs to these targets have either failed clinical trials or have the potential to affect other key CNS physiological processes. As a novel approach, targeting βarr2 function in the DA system might be desirable because through its desensitization of G protein signaling, it can reduce dyskinesias and simultaneously through its signaling ability facilitate locomotion, without potentially affecting other neurotransmitter systems.In the current study we provide evidence supporting the hypothesis that up-regulating βarr2 expression ameliorates LIDs but enhances the therapeutic effects of l-DOPA. We use four different animal models of PD and LIDs to support this notion: (i) a nonconventional mouse model of acute PD symptoms: the bilateral DA-deficient dopamine transporter (DAT)-KO (DDD) mouse (41, 42), (ii) a unilateral 6-hydroxydopamine (6-OHDA)-lesioned mouse model, (iii) a unilateral 6-OHDA–lesioned rat model, and (iv) a bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned nonhuman primate (NHP) model of PD. Using these various animal models we show that deletion of βarr2 enhances LIDs and reduces forward locomotion but overexpression of βarr2 in the striatum reduces LIDs and enhances the therapeutic effects of l-DOPA.     

MicroRNA-216a inhibits neuronal apoptosis in a cellular Parkinson’s disease model by targeting Bax

Metabolic Brain Disease - The study found that microRNAs play an important role in Parkinson’s disease (PD). However, the function of MicroRNA-216a (miR-216a) in PD is unclear. Therefore,...     

Cryptotanshinone ameliorates MPP+-induced oxidative stress and apoptosis of SH-SY5Y neuroblastoma cells: the role of STAT3 in Parkinson’s disease

Metabolic Brain Disease - Cryptotanshinone (CTN) has shown its neuroprotective and anti-inflammatory qualities in non-genetic mouse model of Alzheimer’s disease. According to bioinformatics...     

Effect of entacapone on colon motility and ion transport in a rat model of Parkinson’s disease

AIM: To study the effects of entacapone, a catecholO-methyltransferase inhibitor, on colon motility and electrolyte transport in Parkinson’s disease(PD) rats.METHODS: Distribution and expression of catecholO-methyltransferase(COMT) were measured by immunohistochemistry and Western blotting methods. The colonic smooth muscle motility was examined in vitroby means of a muscle motility recording device. The mucosal electrolyte transport of PD rats was examined by using a short-circuit current(I SC) technique and scanning ion-selective electrode technique(SIET). Intracellular detection of c AMP and c GMP was accomplished by radioimmunoassay testing. RESULTS: COMT was expressed in the colons of both normal and PD rats, mainly on the apical membranes of villi and crypts in the colon. Compared to normal controls, PD rats expressed less COMT. The COMT inhibitor entacapone inhibited contraction of the PD rat longitudinal muscle in a dose-dependent manner. The β2 adrenoceptor antagonist ICI-118,551 blocked this inhibitory effect by approximately 67%(P < 0.01). Entacapone increased mucosal ISC in the colon of rats with PD. This induction was significantly inhibited by apical application of Cl- channel blocker diphenylamine-2, 2’-dicarboxylic acid, basolateral application of Na+-K+-2Cl-co-transporter antagonist bumetanide, elimination of Cl- from the extracellular fluid, as well as pretreatment using adenylate cyclase inhibitor MDL12330 A. As an inhibitor of prostaglandin synthetase, indomethacin can inhibit entacaponeinduced ISC by 45%(P < 0.01). When SIET was applied to measure Cl- flux changes, this provided similar results. Entacapone significantly increased intracellular c AMP content in the colonic mucosa, which was greatly inhibited by indomethacin.CONCLUSION: COMT expression exists in rat colons. The β2 adrenoceptor is involved in the entacaponeinduced inhibition of colon motility. Entacapone induces c AMP-dependent Cl- secretion in the PD rat.     

Trigonelline protects hippocampus against intracerebral Aβ(1–40) as a model of Alzheimer’s disease in the rat: insights into underlying mechanisms

Metabolic Brain Disease - Alzheimer’s disease (AD) is a chronic neurodegenerative disorder and the most common phenotype of dementia. Trigonelline is an alkaloid found in medicinal plants...     

Sudden unexpected death in Parkinson’s disease (SUDPAR): sleep apnea increases risk of heart attack

Sleep and Breathing -     

Glucagon like peptide-1 (GLP-1) likes Alzheimer’s disease

Glucagon-like peptide-1 (GLP-1) is a 30 amino acid long peptide hormone derived from the proglucagon gene and secreted in the distal small intestine when food enters the duodenum. GLP-1 is also produced in the central nervous system (CNS), predominantly in the brainstem, and subsequently transported to a large number of regions in the CNS. Neuronal cells in nucleus tractus solitarius (NTS) can synthesize GLP-1 and extends to hypothalamus, some thalamic and cortical areas. A G protein coupled receptor (GPCR) provides the majority of GLP-1 actions. GLP-1 receptor activation triggers some in vivo signaling pathways.GLP-1 receptor agonists (GLP-1 RA) are used in the treatment diabetes and obesity. GLP-1 stimulates insulin secretion, inhibits glucagon secretion, decreases food intake, reduces appetite, delays gastric emptying, provides weight reduction, and protects β cells from apoptosis. Alzheimer’s disease (AD) is the most prevalent form of dementia. It is characterized by cognitive insufficiencies and behavioral changes that impact memory and learning abilities, daily functioning and quality of life. Hyperinsulinemia and insulin resistance, which are known as pathophysiological features of the T2DM, have also been demonstrated to have significant impact on cognitive impairment.It is thought that GLP-1 affects neurological and cognitive functions, as well as its regulatory effect on glucose metabolism. The pathophysiological relationship between GLP-1 and AD is discussed in this review.     

Raynaud’s phenomenon in undifferentiated connective tissue disease (UCTD)

The aim of this study was to ascertain which clinical and immunological factors are associated with Raynauds phenomenon (RP) in patients with undifferentiated connective tissue disease (UCTD) and to investigate microvascular involvement. A total of 78 patients were evaluated. They all showed symptoms suggestive of a connective tissue disorder (CTD), but did not fulfil the criteria for any of the defined CTDs. They all had a disease duration of at least 1 year. Nailfold capillaroscopy (NC) was performed using a computerised videomicroscope. We diagnosed RP in 52.5% of our patients. Patients with RP showed a higher occurrence of oesophageal dysmotility (p=0.001) and anti-ribonucleoprotein (RNP) antibodies (p=0.004) than those without RP. The distinguishing capillaroscopic characteristics of UCTD patients with RP were widened and irregularly enlarged loops (75 and 55%, respectively), giant capillaries (35%), and less than two haemorrhages per finger (40%). The combination of features indicative of a slow scleroderma pattern was present in 18 of 40 patients with UCTD and RP (p=0.0003). Only 3 of the original 78 patients (3.8%) developed a definite CTD. In none of our patients did we observe avascular areas or changes from the original capillaroscopic pattern during follow-up examination. Our study indicates that patients with UCTD would seem to have a benign form of RP, since they show the absence of cutaneous complications, the existence of a mild microvascular damage and a stable nailfold capillary pattern. Further examinations of these patients will be required in order to confirm our findings.     

Suppression of FoxO1/cell death-inducing DNA fragmentation factor α-like effector A (Cidea) axis protects mouse β-cells against palmitic acid-induced apoptosis

Chronic exposure to free fatty acid (FFA) induces pancreatic β-cell apoptosis, which may contribute to the development of type 2 diabetes. The cell death-inducing DNA fragmentation factor α-like effector (CIDE) family is involved in type 2 diabetes with obesity. In the present study, we found that only apoptosis-inducing FFA upregulated Cidea, and both apoptosis and Cidea were upregulated most strongly by palmitic acid, suggesting that the expression of Cidea is positively correlated with apoptosis. In contrast, there were weak correlations between Cideb and Cidec expression, and apoptosis. Furthermore, suppression of Cidea inhibited palmitic acid-induced apoptosis. Finally, suppression of FoxO1 inhibited palmitic acid-induced Cidea upregulation and apoptosis. These results indicate that Cidea is a critical regulator of FFA-induced apoptosis as a novel downstream target for FoxO1 in β-cells, suggesting that suppression of Cidea is a potentially useful therapeutic approach for protecting against β-cell loss in type 2 diabetes.     

Rheumatoid-like deformities in Parkinson’s disease with 1-year follow-up: case report and literature review

Rheumatoid-like deformities in joints are uncommon in patients with Parkinson’s disease and easy to be misdiagnosed with rheumatoid arthritis. Therefore, unnecessary treatment is often initiated. Here, we report a case of a 60-year-old woman with Parkinson’s disease developing a rheumatoid-like joint deformities, and evaluate 1-year follow-up outcome. We also review the literature and discuss the clinical characteristics, possible pathogenesis, and treatment strategy of these cases.     

Can hyperuricemia predict glycogen storage disease (McArdle’s disease) in rheumatology practice? (Myogenic hyperuricemia)

Clinical Rheumatology - Gout disease is an inflammatory arthritis that arises due to the accumulation of monosodium urate crystals (MSU) around the joints and in tissues. Clinical manifestation of...     

Autoantibodies against complement C1q in patients with Behcet’s disease: association with vascular involvement

Abstract

Aim. The aim of our study was to determine the prevalence of anti-C1q antibodies and their possible association with clinical presentation in Behcet’s disease (BD) patients with special emphasis for patients with vascular involvement.

Methods. Plasma anti-C1q Abs levels were measured using an enzyme-linked immunosorbent assay in 51 BD patients and 25 age- and gender-matched healthy controls.

Results. We found elevated concentrations of anti-C1q more frequently in patients with BD (18 %) than in healthy controls (8 %). The highest prevalence was found in patients with vascular BD (42 %) which was significantly higher than patients without vascular BD and healthy controls (p = 0.025). Furthermore, patients with vascular BD had the highest mean anti-C1q levels when compared to BD patients without vascular involvement or healthy control subjects (p = 0.015). We did not find significant differences in the prevalence of any other organ involvement between BD patients with elevated vs. normal anti-C1q ab levels. Anti-C1q ab levels positively correlated with ESR (r = 0.383, p = 0.006) and negatively with C4 (r = ?0.304, p = 0.030).

Conclusion. In conclusion, we found an increased prevalence of anti-C1q autoantibodies in BD patients with vascular involvement. Further large scale longitudinal studies are required to assess and clarify the significance and the pathogenic role of anti-C1q antibodies in BD and other autoimmune diseases in which vasculitis is a component.     

Peroxisome proliferator-activated receptor α (PPARα) protects against oleate-induced INS-1E beta cell dysfunction by preserving carbohydrate metabolism

Aims/hypothesis  

Pancreatic beta cells chronically exposed to fatty acids may lose specific functions and even undergo apoptosis. Generally, lipotoxicity is triggered by saturated fatty acids, whereas unsaturated fatty acids induce lipodysfunction, the latter being characterised by elevated basal insulin release and impaired glucose responses. The peroxisome proliferator-activated receptor α (PPARα) has been proposed to play a protective role in this process, although the cellular mechanisms involved are unclear.     

The effects simultaneous inhibition of dipeptidyl peptidase-4 and P2X7 purinoceptors in an in vivo Parkinson’s disease model

Metabolic Brain Disease - Loss of dopaminergic neurons following Parkinson’s disease (PD) diminishes quality of life in patients. The present study was carried out to investigate the...