Ethyl-EPA in Huntington disease: potentially relevant mechanism of action

The pathomechanisms involved in the neuronal dysfunction in Huntington disease (HD) are still unresolved and may be heterogeneous. One potential mechanism might be related to the induction of mitochondrial dysfunction in the CNS. This might lead firstly to neuronal dysfunction and finally to the activation of apoptotic pathways. Several compounds, which should alleviate mitochondrial dysfunction, have been tested in preclinical models as well as in clinical trials of different scale. Recently we reported the efficacy of Ethyl-eicosapentaenoic acid (Ethyl-EPA) in patients with HD. Ethyl-EPA is a polyunsaturated fatty acid from the n-3 group, which is in clinical development for HD and melancholic depression. In our trial with Ethyl-EPA in HD responding patients could be characterized by either a lower CAG repeat number or a chorea-predominant clinical expression of the disease. Here we would like to describe some evidence on the potential mechanism of action of Ethyl-EPA in HD. We specifically focus on pathways, which are known to be influenced in HD and are modified by Ethyl-EPA and which points to an involvement of mitochondrial function as a common target. Some attention is given to the NF-kappa B pathway and the c-Jun amino-terminal kinases (JNK) pathway, which both may lead to an activation of the antiproliferative factor p53 and consequently mitochondrial dysfunction. Further the effects of EPA or Ethyl-EPA in preclinical models of HD are described. The evidence from these studies led to the design of phase III clinical trials, which are ongoing.     

Potential drugs and methods for preventing or delaying the progression of Huntington's disease

Huntington's disease (HD) is an autosomal dominant inherited and progressive neurodegenerative disorder with motor dysfunction and cognitive deficits. Although there are no treatments to delay the appearance and the progression of HD, there are potential drugs currently in preclinical and clinical trials that are focused on HD therapy. The signaling pathways involved in HD are not yet clearly elucidated; however, expression of mutant huntingtin protein is considered a key factor in the induction and/or progression of HD. The demonstration that the onset and progression of HD in models of transgenic mice, in particular, are delayed or improved by the application of neurotrophic factors has emphasized their importance in neuroprotection in HD. In addition, other compounds targeting the HD gene or mutant huntingtin protein are currently in preclinical and clinical testing and may show promising neuroprotective effects. There are current patented drugs that are currently being considered as potential therapeutics for HD. These patented drugs may provide promising therapy for HD.     

The role of mitochondrial transition pore, and its modulation, in traumatic brain injury and delayed neurodegeneration after TBI

Following severe traumatic brain injury (TBI), a complex interplay of pathomechanism, such as exitotoxicity, oxidative stress, inflammatory events, and mitochondrial dysfunction occurs. This leads to a cascade of neuronal and axonal pathologies, which ultimately lead to axonal failure, neuronal energy metabolic failure, and neuronal death, which in turn determine patient outcome. For mild and moderate TBI, the pathomechanism is similar but much less frequent and ischemic cell death is unusual, except with mass lesions. Involvement of mitochondria in acute post-traumatic neurodegeneration has been extensively studied during the last decade, and there are a number of investigations implicating the activation of the mitochondrial permeability transition pore (mPTP) as a “critical switch” which determines cell survival after TBI. Opening of the mPTP is modulated by several factors occurring after a severe brain injury. Modern neuroprotective strategies for prevention of the neuropathological squeal of traumatic brain injury have now begun to address the issue of mitochondrial dysfunction, and drugs that protect mitochondrial viability and prevent apoptotic cascade induced by mPTP opening are about to begin phase II and III clinical trials. Cyclosporin A, which has been reported to block the opening of mPTP, showed a significant decrease in mitochondrial damage and intra-axonal cytoskeletal destruction thereby protecting the axonal shaft and blunting axotomy. This review addresses an important issue of mPT activation after severe head injury, its role in acute post-traumatic neurodegeneration, and the rationale for targeting the mPTP in experimental and clinical TBI studies.     

Magnetic resonance imaging as an approach towards identifying neuropathological biomarkers for Huntington's disease

Magnetic Resonance Imaging (MRI), functional MRI (fMRI) and Diffusion Tensor Imaging (DTI) have been central to characterisation of abnormalities in brain structure and function in both clinical and preclinical Huntington's disease (HD). One current challenge in clinical HD research is the identification of sensitive and reliable biomarkers to detect progressive neurodegeneration and neural dysfunction, which could be used to assess the effect of therapeutic intervention on brain structure and function in a HD clinical trial. To this end, both established and novel neuroimaging approaches could potentially provide sensitive, reliable and non-invasive tools to assess long-term and dynamic effects of treatment on specific brain regions, including their microstructure and connectivity. This review examines contributions from structural MRI, fMRI and DTI studies to our current understanding of preclinical and clinical HD, and critically appraises MRI methods potentially suitable for both scientific characterisation and for use as biomarkers in HD clinical trials. A combined neuroimaging approach incorporating structural MRI, fMRI and DTI is yet to be realised in HD clinical trials, however if proven to be sensitive and reliable, these methods could potentially serve as biomarkers for use in future clinical drug trials in HD.     

Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer’s and Parkinson’s diseases

Abnormal interactions and misfolding of synaptic proteins in the nervous system are being extensively explored as important pathogenic events resulting in neurodegeneration in various neurological disorders. These include Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB). In AD, misfolded amyloid β peptide 1–42 (Aβ), a proteolytic product of amyloid precursor protein metabolism, accumulates in the neuronal endoplasmic reticulum and extracellularly as plaques. In contrast, in PD and DLB cases there is abnormal accumulation of α-synuclein in neuronal cell bodies, axons, and synapses. Furthermore, in DLB, Aβ 1–42 may promote α-synuclein accumulation and neurodegeneration. The central event leading to synaptic and neuronal loss in these diseases is not completely clear yet; however, recent advances in the field suggest that nerve damage might result from the conversion of nontoxic monomers to toxic oligomers and protofibrils. The mechanisms by which misfolded Aβ peptide and α-synuclein might lead to synapse loss are currently under investigation. Several lines of evidence support the possibility that Aβ peptide and α-synuclein might interact to cause mitochondrial and plasma membrane damage upon translocation of protofibrils to the membranes. Accumulation of Aβ and α-synuclein oligomers in the mitochondrial membrane might result in the release of cytochrome C with the subsequent activation of the apoptosis cascade. Conversely, the oxidative stress and mitochondrial dysfunction associated with AD and PD may also lead to increased membrane permeability and cytochrome C release, which promotes Aβ and α-synuclein oligomerization and neurodegeneration. Together, these studies suggest that the translocation of misfolded proteins to the mitochondrial membrane might play an important role in either triggering or perpetuating neurodegeneration. The insights obtained from the characterization of this process may be applied to the role of mitochondrial dysfunction in other neurodegenerative disorders, including AD. New evidence may also provide a rationale for the mitochondrial membrane as a target for therapy in a variety of neurodegenerative diseases.     

Huntington’s Disease and Mitochondria

Huntington’s disease (HD) as an inherited neurodegenerative disorder leads to neuronal loss in striatum. Progressive motor dysfunction, cognitive decline, and psychiatric disturbance are the main clinical symptoms of the HD. This disease is caused by expansion of the CAG repeats in exon 1 of the huntingtin which encodes Huntingtin protein (Htt). Various cellular and molecular events play role in the pathology of HD. Mitochondria as important organelles play crucial roles in the most of neurodegenerative disorders like HD. Critical roles of the mitochondria in neurons are ATP generation, Ca²⁺ buffering, ROS generation, and antioxidant activity. Neurons as high-demand energy cells closely related to function, maintenance, and dynamic of mitochondria. In the most neurological disorders, mitochondrial activities and dynamic are disrupted which associate with high ROS level, low ATP generation, and apoptosis. Accumulation of mutant huntingtin (mHtt) during this disease may evoke mitochondrial dysfunction. Here, we review recent findings to support this hypothesis that mHtt could cause mitochondrial defects. In addition, by focusing normal huntingtin functions in neurons, we purpose mitochondria and Huntingtin association in normal condition. Moreover, mHtt affects various cellular signaling which ends up to mitochondrial biogenesis. So, it could be a potential candidate to decline ATP level in HD. We conclude how mitochondrial biogenesis plays a central role in the neuronal survival and activity and how mHtt affects mitochondrial trafficking, maintenance, integrity, function, dynamics, and hemostasis and makes neurons vulnerable to degeneration in HD.     

Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders

Substantial evidence indicates that bioenergetic dysfunction plays either a primary or secondary role in the pathophysiology of cell death in neurodegenerative and neuromuscular disorders, and even in normal aging. Agents that ameliorate bioenergetic defects may therefore be useful in therapy. Creatine, which increases muscle and brain phosphocreatine concentrations, and may inhibit the activation of the mitochondrial permeability transition, protects against neuronal degeneration in transgenic murine models of amyotrophic lateral sclerosis and Huntington's disease and in chemically mediated neurotoxicity. Initial studies of creatine use in humans appear promising; however, further long-term, well-designed trials are needed. Coenzyme Q10, Gingko biloba, nicotinamide, riboflavin, carnitine, lipoic acid, and dichloroacetate are other agents which may have beneficial effects on energy metabolism, but the preclinical and clinical evidence for efficacy in neurological diseases remains limited. These compounds are widely used as dietary supplements; however, they must be subjected to rigorous evaluation through randomized, double-blinded trials to establish efficacy, cost-effectiveness and safety in neurological disorders.     

Mitochondrial dysfunction in schizophrenia: Pathways,mechanisms and implications

Mitochondria play a critical role in regulating cellular functions including bioenergetics, calcium homeostasis, redox signalling, and apoptotic cell death. Mitochondria are also essential to many aspects of neurodevelopment and neuronal functions. However, mitochondrial impairment may affect bioenergetics in the developing brain and alter critical neuronal processes leading to neurodevelopmental abnormalities.Schizophrenia is a chronic and severe neuropsychiatric disorder of neurodevelopmental origin. Immuno-inflammatory pathway is one of the widely appreciated mechanisms that has consistently been implicated in the neurodevelopmental origin of schizophrenia. However, the source of inflammation and the underlying neurobiological mechanisms leading to schizophrenia are yet to be fully ascertained. Recent understanding reveals that perturbation of mitochondrial network dynamics might lead to various nervous system disorders with inflammatory pathologies. Mitochondrial deficit, altered redox balance and chronic low-grade inflammation are evident in schizophrenia. It is hypothesized that oxidative/nitrosative stress responses due to mitochondrial dysfunctions might activate immuno-inflammatory pathways and subsequently lead to neuroprogressive changes in schizophrenia. Herein, we summarise the current understanding of molecular links between mitochondrial dysfunctions and pathogenesis of schizophrenia based on evidence from genomics, proteomics and imaging studies, which together support a role for mitochondrial impairment in the pathogenetic pathways of schizophrenia.     

Protective effects of brain-derived neurotrophic factor against neurotoxicity of 3-nitropropionic acid in rat cortical neurons

Brain-derived neurotrophic factor (BDNF) deficiency has been implicated in pathogenesis of Huntington's disease (HD). 3-Nitropropionic acid (3-NP), an irreversible mitochondrial complex II inhibitor, has been commonly used as a pharmacological model recapitulating HD phenotypes in rodents and nonhuman primates. Herein we test whether BDNF may exert neuroprotective effects against mitochondrial dysfunction caused by 3-NP in primary culture of fetal rat cortical neurons. Preconditioning of neuronal cells with BDNF (100 ng/ml for 8 h) attenuated 3-NP toxicity (2.5 mM for additional 24 h) based on Hoechst and propidium iodide (PI) staining. BDNF effects can be inhibited by the nitric oxide synthase (NOS) inhibitor l-nitroarginine methylester (l-NAME, 100 μM), the cGMP-dependent protein kinase (PKG) inhibitor KT5823 (2 μM), the thioredoxin reductase inhibitor 1-chloro-2,4-dinitrobenzene (DNCB, 5 μM), and a membrane-permeable Bcl-2 inhibitor (12.5 μM). 8-Br-cGMP is a cGMP analogue capable of activating PKG independent of NO. Exogenous application of 8-Br-cGMP (3–30 μM) and purified thioredoxin (3–5 μM) partially mimicked BDNF effects in conferring 3-NP resistance to cortical cells. These results, together with our previous report showing NO donor S-nitrosoglutathione (GSNO)-mediated neuroprotective effects against 3-NP toxicity, suggest that BDNF may protect neurons from mitochondrial dysfunction at least partly via activation of the signaling cascades involving NOS/NO, PKG, thioredoxin and Bcl-2.     

DPP4‐inhibitor improves neuronal insulin receptor function,brain mitochondrial function and cognitive function in rats with insulin resistance induced by high‐fat diet consumption

High‐fat diet (HFD) consumption has been demonstrated to cause peripheral and neuronal insulin resistance, and brain mitochondrial dysfunction in rats. Although the dipeptidyl peptidase‐4 inhibitor, vildagliptin, is known to improve peripheral insulin sensitivity, its effects on neuronal insulin resistance and brain mitochondrial dysfunction caused by a HFD are unknown. We tested the hypothesis that vildagliptin prevents neuronal insulin resistance, brain mitochondrial dysfunction, learning and memory deficit caused by HFD. Male rats were divided into two groups to receive either a HFD or normal diet (ND) for 12 weeks, after which rats in each group were fed with either vildagliptin (3 mg/kg/day) or vehicle for 21 days. The cognitive function was tested by the Morris Water Maze prior to brain removal for studying neuronal insulin receptor (IR) and brain mitochondrial function. In HFD rats, neuronal insulin resistance and brain mitochondrial dysfunction were demonstrated, with impaired learning and memory. Vildagliptin prevented neuronal insulin resistance by restoring insulin‐induced long‐term depression and neuronal IR phosphorylation, IRS‐1 phosphorylation and Akt/PKB‐ser phosphorylation. It also improved brain mitochondrial dysfunction and cognitive function. Vildagliptin effectively restored neuronal IR function, increased glucagon‐like‐peptide 1 levels and prevented brain mitochondrial dysfunction, thus attenuating the impaired cognitive function caused by HFD.     

Cyclosporine-A as a neuroprotective agent against stroke: its translation from laboratory research to clinical application

Stoke remains a leading cause of death and disability with limited treatment options. Extensive research has been aimed at studying cell death events that accompany stroke and how to use these same cell death pathways as potential therapeutic targets for treating the disease. The mitochondrial permeability transition pore (MPTP) has been implicated as a major factor associated with stroke-induced neuronal cell death. MPTP activation and increased permeability has been shown to contribute to the events that lead to cell death. Cyclosporine A (CsA), a widely used immunosuppressant in transplantation and rheumatic medicine, has been recently shown to possess neuroprotective properties through its ability to block the MPTP, which in turn inhibits neuronal damage. This newfound CsA-mediated neuroprotection pathway prompted research on its use to prevent cell death in stroke and other neurological conditions. Preclinical studies are being conducted in hopes of establishing the safety and efficacy guidelines for CsA use in human trials as a potential neuroprotective agent against stroke. In this review, we provide an overview of the current laboratory and clinical status of CsA neuroprotection.     

Kernicterus and the molecular mechanisms of bilirubin-induced CNS injury in newborns

Kernicterus is a devastating, chronic disabling neurological disorder whose central nervous system (CNS) sequelae reflect both a predilection of bilirubin toxicity for neurons (rather than glial cells) and the regional topography of bilirubin-induced neuronal injury that is characterized by prominent basal ganglia, cochlear, and oculomotor nuclei involvement. The molecular pathogenesis of bilirubin-induced neuronal cell injury, although incompletely understood, likely reflects the untoward effects of hazardous unconjugated bilirubin concentrations on plasma, mitochondrial, and/or endoplasmic reticulum (ER) membranes. These membrane perturbations, in turn, might lead to the genesis of neuronal excitotoxicity, mitochondrial energy failure, or increased intracellular calcium concentration [Ca²⁺]_i. These three phenomena are likely to be linked spatially and temporally in the pathogenesis of bilirubininduced neuronal injury. Downstream events triggered by increased [Ca²⁺]_i may include, among others, the activation of proteolytic enzymes, apoptotic pathways, and/or necrosis, the individual occurrence of which is likely a function of the degree and duration of bilirubin exposure. A recent study demonstrates the activation of mitogen-activated protein kinase signal transduction pathways by bilirubin heralding a degree of complexity regarding the molecular mechanism(s) of bilirubin-induced neurotoxicity not previously appreciated. There remains, however, a paucity of data regarding specific effects of bilirubin on intracellular signaling and cell death pathways, particularly in vivo. An enhanced understanding of the molecular pathogenesis of bilirubin-induced neuronal injury will lead to the identification of potential novel interventional strategies to protect the CNS against kernicterus.     

Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases

Abnormal interactions and misfolding of synaptic proteins in the nervous system are being extensively explored as important pathogenic events resulting in neurodegeneration in various neurological disorders. These include Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). In AD, misfolded amyloid beta peptide 1-42 (Abeta), a proteolytic product of amyloid precursor protein metabolism, accumulates in the neuronal endoplasmic reticulum and extracellularly as plaques. In contrast, in PD and DLB cases there is abnormal accumulation of alpha-synuclein in neuronal cell bodies, axons, and synapses. Furthermore, in DLB, Abeta 1-42 may promote alpha-synuclein accumulation and neurodegeneration. The central event leading to synaptic and neuronal loss in these diseases is not completely clear yet; however, recent advances in the field suggest that nerve damage might result from the conversion of nontoxic monomers to toxic oligomers and protofibrils. The mechanisms by which misfolded Abeta peptide and alpha-synuclein might lead to synapse loss are currently under investigation. Several lines of evidence support the possibility that Abeta peptide and alpha-synuclein might interact to cause mitochondrial and plasma membrane damage upon translocation of protofibrils to the membranes. Accumulation of Abeta and alpha-synuclein oligomers in the mitochondrial membrane might result in the release of cytochrome C with the subsequent activation of the apoptosis cascade. Conversely, the oxidative stress and mitochondrial dysfunction associated with AD and PD may also lead to increased membrane permeability and cytochrome C release, which promotes Abeta and alpha-synuclein oligomerization and neurodegeneration. Together, these studies suggest that the translocation of misfolded proteins to the mitochondrial membrane might play an important role in either triggering or perpetuating neurodegeneration. The insights obtained from the characterization of this process may be applied to the role of mitochondrial dysfunction in other neurodegenerative disorders, including AD. New evidence may also provide a rationale for the mitochondrial membrane as a target for therapy in a variety of neurodegenerative diseases.     

Regulation of ceramide-induced neuronal death: cell metabolism meets neurodegeneration

The present review explores the role of ceramides in neuronal apoptosis, as well as the recent discovery of the signaling pathways involved in this process placing particular emphasis on the correlation between cellular metabolism and neuronal death. Endogenous levels of ceramides are increased following various pro-apoptotic stimuli which have been identified as potential causes of chronic and acute neurodegenerative diseases. Ceramides induce changes in multiple enzymes and cell signaling components. The early inhibition of the neuronal survival pathway regulated by phosphatidil-inositol-3-kinase/protein kinase B or AKT mediated by ceramide may be a relevant early event in the decision of neuronal survival/death. It may perturb several molecular and metabolic functions. In particular it might decrease glycolysis through rapid modulation of hexokinase activity. This would in turn generate limited amounts of mitochondrial substrates leading to mitochondrial dysfunction and neuronal apoptosis. Subtle and early metabolic alterations caused by inhibition of the PI3K/AKT pathway mediated by ceramide may potentially work with genes associated with neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Together they may be determinant steps in downstream events leading to neuronal apoptosis. Therefore, reinforcement of the PI3K/AKT pathway could constitute an important neuroprotective strategy.     

亨廷顿病基因治疗研究进展

亨廷顿病是一种以运动、认知和精神障碍为主要表现的遗传性中枢神经系统变性疾病,其致病基因IT15突变可引起胞嘧啶腺嘌呤鸟嘌呤(CAG)三核苷酸重复序列异常扩增,导致所编码的亨廷顿蛋白构象变化并产生神经毒性作用。亨廷顿病的基因治疗目前尚处于临床前阶段,主要包括基因沉默、诱导突变亨廷顿蛋白清除、导入神经营养因子基因,以及纠正突变型亨廷顿蛋白的毒性作用所致的基因转录、信号转导和线粒体代谢紊乱等。本文尝试对亨廷顿病的基因治疗研究进展简要叙述。     

Bioenergetic dysfunction in Huntington's disease human cybrids

In this work we studied the mitochondrial-associated metabolic pathways in Huntington's disease (HD) versus control (CTR) cybrids, a cell model in which the contribution of mitochondrial defects from patients is isolated. HD cybrids exhibited an interesting increase in ATP levels, when compared to CTR cybrids. Concomitantly, we observed increased glycolytic rate in HD cybrids, as revealed by increased lactate/pyruvate ratio, which was reverted after inhibition of glycolysis. A decrease in glucose-6-phosphate dehydrogenase activity in HD cybrids further indicated decreased rate of the pentose-phosphate pathway. ATP levels of HD cybrids were significantly decreased under glycolysis inhibition, which was accompanied by a decrease in phosphocreatine. Nevertheless, pyruvate supplementation could not recover HD cybrids' ATP or phosphocreatine levels, suggesting a dysfunction in mitochondrial use of that substrate. Oligomycin also caused a decrease in ATP levels, suggesting a partial support of ATP generation by the mitochondria. Nevertheless, mitochondrial NADH/NAD_t levels were decreased in HD cybrids, which was correlated with a decrease in pyruvate dehydrogenase activity and protein expression, suggesting decreased tricarboxylic acid cycle (TCA) input from glycolysis. Interestingly, the activity of alpha-ketoglutarate dehydrogenase, a critical enzyme complex that links the TCA to amino acid synthesis and degradation, was increased in HD cybrids. In accordance, mitochondrial levels of glutamate were increased and alanine was decreased, whereas aspartate and glutamine levels were unchanged in HD cybrids. Conversely, malate dehydrogenase activity from total cell extracts was unchanged in HD cybrids. Our results suggest that inherent dysfunction of mitochondria from HD patients affects cellular bioenergetics in an otherwise functional nuclear background.     

Curcumin Nanoparticles Attenuate Neurochemical and Neurobehavioral Deficits in Experimental Model of Huntington’s Disease

Till date, an exact causative pathway responsible for neurodegeneration in Huntington’s disease (HD) remains elusive; however, mitochondrial dysfunction appears to play an important role in HD pathogenesis. Therefore, strategies to attenuate mitochondrial impairments could provide a potential therapeutic intervention. In the present study, we used curcumin encapsulated solid lipid nanoparticles (C-SLNs) to ameliorate 3-nitropropionic acid (3-NP)-induced HD in rats. Results of MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) assay and succinate dehydrogenase (SDH) staining of striatum revealed a marked decrease in Complex II activity. However, C-SLN-treated animals showed significant increase in the activity of mitochondrial complexes and cytochrome levels. C-SLNs also restored the glutathione levels and superoxide dismutase activity. Moreover, significant reduction in mitochondrial swelling, lipid peroxidation, protein carbonyls and reactive oxygen species was observed in rats treated with C-SLNs. Quantitative PCR and Western blot results revealed the activation of nuclear factor-erythroid 2 antioxidant pathway after C-SLNs administration in 3-NP-treated animals. In addition, C-SLN-treated rats showed significant improvement in neuromotor coordination when compared with 3-NP-treated rats. Thus, the results of this study suggest that C-SLNs administration might be a promising therapeutic intervention to ameliorate mitochondrial dysfunctions in HD.