The α2 adrenoceptor antagonist idazoxan alleviates l‐DOPA‐induced dyskinesia by reduction of striatal dopamine levels: an in vivo microdialysis study in 6‐hydroxydopamine‐lesioned rats

l ‐DOPA‐induced dyskinesia is characterised by debilitating involuntary movement, which limits quality of life in patients suffering from Parkinson’s disease. Here, we investigate effects of the α₂ adrenoceptor antagonist idazoxan on l ‐DOPA‐induced dyskinesia as well as on alterations of extracellular l ‐DOPA and dopamine (DA) levels in the striatum in dyskinetic rats. Male Wistar rats were unilaterally lesioned with 6‐hydroxydopamine and subsequently treated with l ‐DOPA/benserazide to induce stable dyskinetic movements. Administration of idazoxan [(9 mg/kg, intraperitoneal (i.p.)] significantly alleviated l ‐DOPA‐induced dyskinesia, whereas idazoxan (3 mg/kg, i.p.) did not affect dyskinetic behaviour. Bilateral in vivo microdialysis revealed that idazoxan 9 mg/kg reduces extracellular peak l ‐DOPA levels in the lesioned and intact striatum as well as DA levels in the lesioned striatum. In parallel, the exposure to idazoxan in the striatum was monitored. Furthermore, no idazoxan and l ‐DOPA drug–drug interaction was found in plasma, brain tissue and CSF. In conclusion, the decrease of l ‐DOPA‐derived extracellular DA levels in the lesioned striatum significantly contributes to the anti‐dyskinetic effect of idazoxan.     

Impairment of oxidative stress-induced heme oxygenase-1 expression by the defect of Parkinson-related gene of PINK1

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Mutation in the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) gene causes an autosomal recessive form of PD. However, the etiology related to PINK1 is still not clear. Here, we examined the effect of PINK1 on heme oxygenase (HO)-1 induction in SH-SY5Y neuronal cells following H(2)O(2) or 1-methyl-4-phenylpyridinium (MPP(+)) treatment. The HO-1 induction in response to H(2)O(2) and MPP(+) treatment was impaired by the expression of recombinant PINK1 G309D mutant. PINK1 G309D mutation increased the apoptosis of SH-SY5Y cells following H(2)O(2) treatment and cell survival was rescued by the over-expression of HO-1 using adenovirus (Ad) infection. In addition, knockdown of tumor necrosis factor receptor-associated protein-1 (TRAP1), which is the substrate of PINK1 kinase, in SH-SY5Y cells also inhibited the expression of HO-1 in response to oxidative stress. The up-regulation of TRAP1 expression following H(2)O(2) treatment was inhibited by the expression of recombinant PINK1 G309D mutant. The H(2)O(2)-induced HO-1 induction was Akt- and ERK-dependent. The phosphorylation of ERK and Akt but not p38 was inhibited in cells expressing the PINK1 G309D mutant and knockdown of TRAP1. These results indicate a novel pathway by which the defect of PINK1 inhibits the oxidative stress-induced HO-1 production. Impairment of HO-1 production following oxidative stress may accelerate the dopaminergic neurodegeneration in Parkinson patients with PINK1 defect.     

Dopaminergic deficiency in mice with reduced levels of the dual-specificity tyrosine-phosphorylated and regulated kinase 1A, Dyrk1A(+/-)

The dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1A) gene encodes a protein kinase known to play a critical role in neurodevelopment. Mice with one functional copy of Dyrk1A (Dyrk1A(+/-)) display a marked hypoactivity and altered gait dynamics in basal conditions and in novel environments. Dopamine (DA) is a key neurotransmitter in motor behavior and genetic deletion of certain genes directly related to the dopaminergic system has a strong impact on motor activity. We have studied the effects of reduced Dyrk1A expression on the function of the nigrostriatal dopaminergic system. To characterize the dopaminergic system in DYRK1A(+/-) mice, we have used behavioral, pharmacological, histological, neurochemical and neuroimaging (microPET) techniques in a multidisciplinary approach. Dyrk1A(+/-) mice exhibited decreased striatal DA levels, reduced number of DA neurons in the substantia nigra pars compacta, as well as altered behavioral responses to dopaminergic agents. Moreover, microdialysis experiments revealed attenuated striatal DA release and positron emission tomography scan display reduced forebrain activation when challenged with amphetamine, in Dyrk1A(+/-) compared with wild-type mice. These data indicate that Dyrk1A is essential for a proper function of nigrostriatal dopaminergic neurons and suggest that Dyrk1A(+/-) mice can be used to study the pathogenesis of motor disorders involving dopaminergic dysfunction.     

Activation of 5-HT(1A) but not 5-HT(1B) receptors attenuates an increase in extracellular dopamine derived from exogenously administered L-DOPA in the striatum with nigrostriatal denervation

In order to determine whether L-DOPA-derived extracellular dopamine (DA) in the striatum with dopaminergic denervation is affected by activation of serotonin autoreceptors (5-HT(1A) and 5-HT(1B) receptors), we applied in vivo brain microdialysis technique to 6-hydroxydopamine-lesioned rats and examined the effects of the selective 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the selective 5-HT(1B) receptor agonist CGS-12066 A on L-DOPA-derived extracellular DA levels. Single L-DOPA injection (50 mg/kg i.p.) caused a rapid increase and a following decrease of extracellular DA, with a peak value at 100 min after L-DOPA injection. Pretreatment with both 0.3 mg/kg and 1 mg/kg 8-OH-DPAT (i.p.) significantly attenuated an increase in L-DOPA-derived extracellular DA and the times of peak DA levels were prolonged to 150 min and 225 min after L-DOPA injection, respectively. These 8-OH-DPAT-induced changes in L-DOPA-derived extracellular DA were antagonized by further pretreatment with WAY-100635, a selective 5-HT(1A) antagonist. In contrast, intrastriatal perfusion with the 5-HT(1B) agonist CGS-12066 A (10 nM and 100 nM) did not induce any changes in L-DOPA-derived extracellular DA. Thus, stimulation of 5-HT(1A) but not 5-HT(1B) receptors attenuated an increase in extracellular DA derived from exogenous L-DOPA. These results support the hypothesis that serotonergic neurons are primarily responsible for the storage and release of DA derived from exogenous L-DOPA in the absence of dopaminergic neurons.     

Nurr1 (NR4A2) regulates Alzheimer’s disease‐related pathogenesis and cognitive function in the 5XFAD mouse model

The orphan nuclear receptor Nurr1 (also known as NR4A2) is critical for the development and maintenance of midbrain dopaminergic neurons, and is associated with Parkinson's disease. However, an association between Nurr1 and Alzheimer's disease (AD)‐related pathology has not previously been reported. Here, we provide evidence that Nurr1 is expressed in a neuron‐specific manner in AD‐related brain regions; specifically, it is selectively expressed in glutamatergic neurons in the subiculum and the cortex of both normal and AD brains. Based on Nurr1’s expression patterns, we investigated potential functional roles of Nurr1 in AD pathology. Nurr1 expression was examined in the hippocampus and cortex of AD mouse model and postmortem human AD subjects. In addition, we performed both gain‐of‐function and loss‐of‐function studies of Nurr1 and its pharmacological activation in 5XFAD mice. We found that knockdown of Nurr1 significantly aggravated AD pathology while its overexpression alleviated it, including effects on Aβ accumulation, neuroinflammation, and neurodegeneration. Importantly, 5XFAD mice treated with amodiaquine, a highly selective synthetic Nurr1 agonist, showed robust reduction in typical AD features including deposition of Aβ plaques, neuronal loss, microgliosis, and impairment of adult hippocampal neurogenesis, leading to significant improvement of cognitive impairment. These in vivo and in vitro findings suggest that Nurr1 critically regulates AD‐related pathophysiology and identify Nurr1 as a novel AD therapeutic target.     

Role of sphingosine 1-phosphate and lysophosphatidic acid in fibrosis

This review highlights an emerging role for sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) in many different types of fibrosis. Indeed, both LPA and S1P are involved in the multi-process pathogenesis of fibrosis, being implicated in promoting the well-established process of differentiation of fibroblasts to myofibroblasts and the more controversial epithelial–mesenchymal transition and homing of fibrocytes to fibrotic lesions. Therefore, targeting the production of these bioactive lysolipids or blocking their sites/mechanisms of action has therapeutic potential. Indeed, LPA receptor 1 (LPA₁) selective antagonists are currently being developed for the treatment of fibrosis of the lung as well as a neutralising anti-S1P antibody that is currently in Phase 1 clinical trials for treatment of age related macular degeneration. Thus, LPA- and S1P-directed therapeutics may not be too far from the clinic. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.     

New approaches for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is the most prevalent chronic neurodegenerative disease. Current approved therapies are symptomatic treatments having some effect on cognitive function. Therapies that target β-amyloid (Aβ) have been the focus of efforts to develop a disease modification treatment for AD but these approaches have failed to show any clinical benefit so far. Beyond the ‘Aβ hypothesis’, there are a number of newer approaches to treat AD with neuroinflammation emerging as a very active area of research based on risk gene analysis. This short review will summarize approved drug therapies, recent clinical trials and new approaches for the treatment of AD.     

The pro-tumorigenic effects of metabolic alterations in glioblastoma including brain tumor initiating cells

De-regulated cellular energetics is an emerging hallmark of cancer with alterations to glycolysis, oxidative phosphorylation, the pentose phosphate pathway, lipid oxidation and synthesis and amino acid metabolism. Understanding and targeting of metabolic reprogramming in cancers may yield new treatment options, but metabolic heterogeneity and plasticity complicate this strategy. One highly heterogeneous cancer for which current treatments ultimately fail is the deadly brain tumor glioblastoma. Therapeutic resistance, within glioblastoma and other solid tumors, is thought to be linked to subsets of tumor initiating cells, also known as cancer stem cells. Recent profiling of glioblastoma and brain tumor initiating cells reveals changes in metabolism, as compiled here, that may be more broadly applicable. We will summarize the profound role for metabolism in tumor progression and therapeutic resistance and discuss current approaches to target glioma metabolism to improve standard of care.     

Multifaceted applications of nanomaterials in cell engineering and therapy

Nanomaterials with superior physiochemical properties have been rapidly developed and integrated in every aspect of cell engineering and therapy for translating their great promise to clinical success. Here we demonstrate the multifaceted roles played by innovatively-designed nanomaterials in addressing key challenges in cell engineering and therapy such as cell isolation from heterogeneous cell population, cell instruction in vitro to enable desired functionalities, and targeted cell delivery to therapeutic sites for prompting tissue repair. The emerging trends in this interdisciplinary and dynamic field are also highlighted, where the nanomaterial-engineered cells constitute the basis for establishing in vitro disease model; and nanomaterial-based in situ cell engineering are accomplished directly within the native tissue in vivo. We will witness the increasing importance of nanomaterials in revolutionizing the concept and toolset of cell engineering and therapy which will enrich our scientific understanding of diseases and ultimately fulfill the therapeutic demand in clinical medicine.     

Endogenous opiates and behavior: 2010

This paper is the thirty-third consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2010 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior (Section 2), and the roles of these opioid peptides and receptors in pain and analgesia (Section 3); stress and social status (Section 4); tolerance and dependence (Section 5); learning and memory (Section 6); eating and drinking (Section 7); alcohol and drugs of abuse (Section 8); sexual activity and hormones, pregnancy, development and endocrinology (Section 9); mental illness and mood (Section 10); seizures and neurologic disorders (Section 11); electrical-related activity and neurophysiology (Section 12); general activity and locomotion (Section 13); gastrointestinal, renal and hepatic functions (Section 14); cardiovascular responses (Section 15); respiration (Section 16); and immunological responses (Section 17).     

Diabetes as a risk factor for Alzheimer’s disease in the Middle East and its shared pathological mediators

The incidence of Alzheimer’s disease (AD) has risen exponentially worldwide over the past decade. A growing body of research indicates that AD is linked to diabetes mellitus (DM) and suggests that impaired insulin signaling acts as a crucial risk factor in determining the progression of this devastating disease. Many studies suggest people with diabetes, especially type 2 diabetes, are at higher risk of eventually developing Alzheimer's dementia or other dementias. Despite nationwide efforts to increase awareness, the prevalence of Diabetes Mellitus (DM) has risen significantly in the Middle East and North African (MENA) region which might be due to rapid urbanization, lifestyle changes, lack of physical activity and rise in obesity. Growing body of evidence indicates that DM and AD are linked because both conditions involve impaired glucose homeostasis and altered brain function. Current theories and hypothesis clearly implicate that defective insulin signaling in the brain contributes to synaptic dysfunction and cognitive deficits in AD. In the periphery, low-grade chronic inflammation leads to insulin resistance followed by tissue deterioration. Thus insulin resistance acts as a bridge between DM and AD. There is pressing need to understand on how DM increases the risk of AD as well as the underlying mechanisms, due to the projected increase in age related disorders. Here we aim to review the incidence of AD and DM in the Middle East and the possible link between insulin signaling and ApoE carrier status on Aβ aggregation, tau hyperphosphorylation, inflammation, oxidative stress and mitochondrial dysfunction in AD. We also critically reviewed mutation studies in Arab population which might influence DM induced AD. In addition, recent clinical trials and animal studies conducted to evaluate the efficiency of anti-diabetic drugs have been reviewed.     

The Endo-lysosomal System in Parkinson’s Disease: Expanding the Horizon

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, and its prevalence is increasing with age. A wealth of genetic evidence indicates that the endo-lysosomal system is a major pathway driving PD pathogenesis with a growing number of genes encoding endo-lysosomal proteins identified as risk factors for PD, making it a promising target for therapeutic intervention. However, detailed knowledge and understanding of the molecular mechanisms linking these genes to the disease are available for only a handful of them (e.g. LRRK2, GBA1, VPS35). Taking on the challenge of studying poorly characterized genes and proteins can be daunting, due to the limited availability of tools and knowledge from previous literature. This review aims at providing a valuable source of molecular and cellular insights into the biology of lesser-studied PD-linked endo-lysosomal genes, to help and encourage researchers in filling the knowledge gap around these less popular genetic players. Specific endo-lysosomal pathways discussed range from endocytosis, sorting, and vesicular trafficking to the regulation of membrane lipids of these membrane-bound organelles and the specific enzymatic activities they contain. We also provide perspectives on future challenges that the community needs to tackle and propose approaches to move forward in our understanding of these poorly studied endo-lysosomal genes. This will help harness their potential in designing innovative and efficient treatments to ultimately re-establish neuronal homeostasis in PD but also other diseases involving endo-lysosomal dysfunction.