Is peripartum anhedonia a missing target?

The perinatal period is an extremely delicate phase that can involve a high risk for onset of depressive disorders. The Edinburgh Postnatal Depression Scale (EPDS) is a widely validated instrument for assessing perinatal depressive symptoms, including the dimension of anhedonia. There are studies suggesting that the neural mechanism underlying the occurrence of anhedonia in patients with major depressive disorder (MDD) and bipolar depression (BD) might be distinct. Anhedonia seems to represent a more stable and frequent symptom in women with postpartum bipolar relative to unipolar depressive disorder and is associated with significantly higher depressive symptom severity. Perinatal medicine is an important component of women's health. Treatment of anhedonia can be challenging, and the most effective treatment can be a combination of psychotherapy and medication, but the screening of anhedonia in peripartum women can prevent the development of other psychiatric disorders and maladaptive behaviors.     

Does diabetes mellitus target motor neurons?

A pattern of peripheral neurodegeneration occurs in chronic diabetes mellitus in which an early, but selective retraction of distal axons may occur prior to any irretrievable neuronal loss. Clinical observations suggest that sensory systems undergo damage before those of motor neurons. In this work, we examined the fate of the spinal motor neuron in a long-term chronic model of experimental (streptozotocin-induced) diabetes already known to be associated with substantial loss of sensory neurons. The integrity, physiological function, and critical forms of protein expression of the full motor neuron tree was examined in mice exposed to 8 months of diabetes. Motor neurons developed progressive features of distal loss of axonal terminals but without perikaryal dropout, indicating distal axon retraction. While numbers and caliber of motor neuron perikarya and their nerve trunk axons were preserved, axons developed conduction velocity slowing, loss of motor units and neuromuscular junctions, and compensatory single motor unit action potential enlargement. Four critical proteins directly linked to diabetic complications were altered in motor neurons of diabetic mice: an elevated perikaryal expression of RAGE and PARP, molecules associated with cellular stress, along with concurrent rises in HSP-27 and pAKT, molecules alternatively identified with neuroprotective survival. Moreover, Akt mRNA was increased in diabetic lumbar spinal cords. Overall these findings indicate that although motor neurons are resistant to irretrievable dropout, they are targeted nonetheless by diabetes and gradually withdraw their terminals from distal innervation.     

ΔN-Bcl-xL,a therapeutic target for neuroprotection

The B-cell lymphoma-extra large(Bcl-x L) is a mitochondrial anti-apoptotic protein that plays a role in neuroprotection. However, during excitotoxic stimulation, Bcl-x L undergoes caspase-dependent cleavage and produces a fragmented form, ΔN-Bcl-x L. Accumulation of ΔN-Bcl-x L is associated with mitochondrial dysfunction and neuronal death. Therefore, strategies to inhibit the activity or formation of ΔN-Bclx L protect the brain against excitotoxic injuries. Our team found that the pharmacological inhibitor ABT-737 exerts dose dependent effects in primary neurons. When primary hippocampal neurons were treated with 1 μM ABT-737, glutamate-mediated mitochondrial damage and neuronal death were exacerbated, whereas 10 n M ABT-737, a 100-fold lower concentration, protected mitochondrial function and enhanced neuronal viability against glutamate toxicity. In addition, we suggested acute vs. prolonged formation of ΔN-Bcl-x L may have different effects on mitochondrial or neuronal functions. Unlike acute production of ΔN-Bcl-x L by glutamate, overexpression of ΔN-Bcl-x L did not cause drastic changes in neuronal viability. We predicted that neurons undergo adaptation and may activate altered metabolism to compensate for ΔN-Bcl-x L-mediated mitochondrial dysfunction. Although the detailed mechanism of ABT-mediated neurotoxicity neuroprotection is still unclear, our study shows that the mitochondrial membrane protein ΔN-Bcl-x L is a central target for interventions.     

Does target viewing time influence perceived reachability?

This study examined the influence of target viewing time on perceived (estimates of) reachability. Right-handed participants were asked to judge the simulated reachability of midline targets using their dominant limb in viewing conditions of 150 ms, 500 ms, 1 s and 2 s. Responses were compared to actual maximum reach. In reference to percent error, interestingly, the 150 ms condition revealed the least error at peripersonal targets and the most inaccuracy with distal (extrapersonal) targets. This condition was also distinct with a significant overestimation bias -- a common observation in earlier studies. However, with increasing viewing time this bias was reduced. These data provide evidence that 150 ms is effective for estimating reach within one's general peripersonal workspace. However, with judgments distal from that point, more time enhanced accuracy, with 500 ms and 1 s being optimal. Overall results are discussed relative to perceptual effectiveness in programming reaching movements.     

Nodal proteins are target antigens in Guillain-Barré syndrome

Neurofascin-186 (NF186), neuronal cell adhesion molecule (NrCAM), and gliomedin are adhesion molecules playing a central role in the formation of nodes of Ranvier. In Guillain-Barré syndrome (GBS), immune attack toward the nodes may participate in the disabilities. Autoantibodies to NF186 and gliomedin have been detected in a rat model of GBS. Here, we investigated the prevalence of antibodies against nodal adhesion molecules in patients with GBS or chronic inflammatory demyelinating polyneuropathy (CIDP). Sera from 100 GBS patients, 50 CIDP patients, 80 disease controls, and 50 healthy controls were tested for their ability to bind the nodes of Ranvier. To characterize the antigens, we performed cell binding assays against NF186, gliomedin, contactin, and NrCAM. We found that 43% of patients with GBS and 30% of patients with CIDP showed IgG fixation at nodes or paranodes. In eight patients with GBS or CIDP, we identified that IgG antibodies recognized the native extracellular domain of NF186, gliomedin, or contactin. Also, 29 patients showed IgM against nodal adhesion molecules. However, we did not detect IgM fixation at nodes or paranodes. Antibodies to gliomedin or NF186 were mostly detected in demyelinating and axonal GBS, respectively. The adsorption of the antibodies to their soluble antigens abolished IgG deposition at nodes and paranodes in nerves, indicating these were specific to NF186, gliomedin, and contactin. In conclusion, gliomedin, NF186, and contactin are novel target antigens in GBS. At nodes, additional epitopes are also the targets of IgG. These results suggest that antibody attack against nodal antigens participates in the etiology of GBS.     

Is the GABAB heterodimer a good drug target?

GABA_B receptors are a member of the G protein-coupled family of receptors which are generally considered to be excellent drug targets. Cloning of the GABA_B receptor demonstrated that, unlike other G protein-coupled receptors, it is an obligate heterodimer. Drugs acting at GABA_B receptors have the potential to treat a wide variety of diseases. Activation of the receptors may have utility in the treatment of pain, drug-dependence, and anxiety, whereas blockade of receptors may have benefit in cognitive disorders and depression. To date, development of drugs has been hampered by the lack of receptor subtypes and the inability to separate therapeutic benefit from side effects such as sedation. Recently, novel compounds that act via an allosteric mechanism have been identified and are providing hope that future drugs may be developed that target this receptor.     

α-Synuclein phosphorylation as a therapeutic target in Parkinson's disease

Phosphorylation is a key post-translational modification necessary for normal cellular signaling and, therefore, lies at the heart of cellular function. In neurodegenerative disorders, abnormal hyperphosphorylation of pathogenic proteins is a common phenomenon that contributes in important ways to the disease process. A prototypical protein that is hyperphosphorylated in the brain is α-synuclein (α-syn) - found in Lewy bodies and Lewy neurites - the pathological hallmarks of Parkinson's disease (PD) and other α-synucleinopathies. The genetic linkage of α-syn to PD as well as its pathological association in both genetic and sporadic cases have made it the primary protein of interest. In understanding how α-syn dysfunction occurs, increasing focus is being placed on its abnormal aggregation and the contribution of phosphorylation to this process. Studies of both the kinases and phosphatases that regulate α-syn phosphorylation are beginning to reveal the roles of this post-translational modification in disease pathogenesis. Modulation of α-syn phosphorylation may ultimately prove to be a viable strategy for disease-modifying therapeutic interventions. In this review, we explore mechanisms related to α-syn phosphorylation, its biophysical and functional consequences, and its role in neurodegeneration.     

Does monocular viewing improve target detection in hemispatial neglect?

Experimental animals with large posterior-cortical lesions develop disturbances of visual perception and visually-guided behavior in the contralateral space, resembling the syndrome of unilateral spatial neglect (USN) in humans. The visuo-motor performance in the ignored space is recovered some time following additional lesion inflicted to the contralesional superior colliculus or section of the intercollicular pathways. Based on the model that explains this recovery by disinhibition of the ipsilesional superior colliculus (the 'Sprague effect') Posner and Rafal [37] proposed that ipsilesional monocular occlusion could possibly reduce the 'tone' of contralesional collicular neurons thereby removing an important contributor of hemineglect. A group of twenty-six right-hemisphere-damaged patients with USN was given a cancellation task under binocular and monocular (left and right) viewing conditions. Thirteen patients showed amelioration of left hemineglect in conditions of left-monocular viewing, as compared to the baseline binocular state. Although this result superficially resembles the Sprague effect, two patients benefited from right-monocular viewing whereas eleven patients showed no significant change in either right or left viewing conditions. The possible role of structures mediating interocular differences in target detection in cases of right hemisphere damage is discussed. It is suggested that even if the Sprague effect contributes to the salubrious influence of monocular viewing it is hardly the single factor involved.     

Interleukin-1: an important target for perinatal neuroprotection?

Perinatal inflammation is a significant risk factor for lifelong neurodevelopmental impairments such as cerebral palsy. Extensive clinical and preclinical evidence links the severity and pattern of perinatal inflammation to impaired maturation of white and grey matters and reduced brain growth. Multiple pathways are involved in the pathogenesis of perinatal inflammation. However, studies of human and experimental perinatal encephalopathy have demonstrated a strong causative link between perinata...     

Does monocular viewing improve target detection in hemispatial neglect?

Experimental animals with large posterior-cortical lesions develop disturbances of visual perception and visually-guided behavior in the contralateral space, resembling the syndrome of unilateral spatial neglect (USN) in humans. The visuo-motor performance in the ignored space is recovered some time following additional lesion inflicted to the contralesional superior colliculus (SC) or section of the intercollicular pathways. Based on the model that explains this recovery by disinhibition of the ipsilesional SC (the 'Sprague effect') Posner and Rafal [37] proposed that ipsilesional monocular occlusion could possibly reduce the 'tone' of contralesional collicular neurons thereby removing an important contributor of hemineglect. A group of twenty-six right-hemisphere-damaged patients with USN was given a cancellation task under binocular and monocular (left and right) viewing conditions. Thirteen patients showed amelioration of left hemineglect in conditions of left-monocular viewing, as compared to the baseline binocular state. Although this result superficially resembles the Sprague effect, two patients benefited from right-monocular viewing whereas eleven patients showed no significant change in either right or left viewing conditions. The possible role of structures mediating interocular differences in target detection in cases of right hemisphere damage is discussed. It is suggested that even if the Sprague effect contributes to the salubrious influence of monocular viewing it is hardly the single factor involved.     

Ganglioside complexes as new target antigens in Guillain-Barré syndrome

Antibodies specific for a complex of gangliosides GD1a and GD1b (GD1a/GD1b) were found in sera from eight of 100 patients with Guillain-Barre syndrome (GBS) by the use of enzyme-linked immunosorbent assay and thin-layer chromatogram immunostaining. Those sera also had antibody activities to such ganglioside complexes as GD1a/GM1, GD1b/GT1b, and GM1/GT1b but had little or no reactivity to the each isolated antigen. Clustered epitopes of the ganglioside complex in the plasma membrane may be targeted by such an antibody, and interaction between the antibody and ganglioside complex may induce the neuropathy.     

Is alpha-synuclein pathology a target for treatment of neurodegenerative disorders?

Since the discovery that mutations of alpha-synuclein (AS) gene are responsible for rare forms of familiar Parkinson's disease this synaptic protein attracted increased interest. AS is the main constituent of Lewy bodies. In spite the physiological function is still unclear there is an ongoing discussion if over-expression is already dangerous, or if toxicity is subjected to oligomers, protofibrilles or mature aggregates. The fact that the central hydrophobic part of AS is a constituent of amyloid plaques in Alzheimer patients and the finding that a majority of AD patients have Lewy bodies and Lewy neurites in specific brain areas, raised our interest in the possible contribution of AS to pathogenesis of AD. Beta-synuclein (betaS) a protein of the same gene family seems to be a naturally occurring anti aggregatory factor preventing AS aggregation in vitro and in vivo. The N-terminal amino acid sequence 1 to 15 is responsible for this effect. Based on this finding we synthesized a peptide library with different sequence variations. Several of these peptides displayed distinct neuroprotective activity in tissue culture models of neurodegeneration induced by oxidative stress or Abeta1-42. In spite these peptides have a short half-life, in vivo significant reduction in brain plaque load and improvement of behavioral deficits was demonstrated in an APP-tg mouse model after intranasal treatment for 2 months. KEGV, the shortest sequence was also active after intraperitoneal application. Neuroprotective data in tissue cultures and results from transgenic mice are some how in conflict because in vitro effects can not be explained by the antiaggregatory potential, but most likely by interaction of betaS derivates with anti-apoptotic PI3/Akt cell signaling or interference with anti-oxidative pathways (JNK/JIB). The possibility that such betaS derived peptidomimetics might act as neuroprotectants and at the same time prevent protein missfolding suggests possible therapeutic usefulness in different neurodegenerative disorders.     

The Epigenome as a therapeutic target for Parkinson’s disease

Parkinsons disease(PD) is a common,progressive neurodegenerative disease characterised by degeneration of nigrostriatal dopaminergic neurons,aggregation of α-synuclein and motor symptoms.Current dopamine-replacement strategies provide symptomatic relief,however their effectiveness wear off over time and their prolonged use leads to disabling side-effects in PD patients.There is therefore a critical need to develop new drugs and drug targets to protect dopaminergic neurons and their axons from degeneration in PD.Over recent years,there has been robust evidence generated showing that epigenetic dysregulation occurs in PD patients,and that epigenetic modulation is a promising therapeutic approach for PD.This article first discusses the present evidence implicating global,and dopaminergic neuron-specific,alterations in the methylome in PD,and the therapeutic potential of pharmacologically targeting the methylome.It then focuses on another mechanism of epigenetic regulation,histone acetylation,and describes how the histone acetyltransferase(HAT) and histone deacetylase(HDAC) enzymes that mediate this process are attractive therapeutic targets for PD.It discusses the use of activators and/or inhibitors of HDACs and HATs in models of PD,and how these approaches for the selective modulation of histone acetylation elicit neuroprotective effects.Finally,it outlines the potential of employing small molecule epigenetic modulators as neuroprotective therapies for PD,and the future research that will be required to determine and realise this therapeutic potential.     

Myeloperoxidase: a new target for the treatment of stroke?

Myeloperoxidase is an important inflammatory factor in the myeloid system,primarily expressed in neutrophils and microglia.Myeloperoxidase and its active products participate in the occurrence and development of hemorrhagic and ischemic stroke,including damage to the blood-brain barrier and brain.As a specific inflammatory marker,myeloperoxidase can be used in the evaluation of vascular disease occurrence and development in stroke,and a large amount of experimental and clinical data has indicated that the inhibition or lack of myeloperoxidase has positive impacts on stroke prognosis.Many studies have also shown that there is a correlation between the overexpression of myeloperoxidase and the risk of stroke.The occurrence of stroke not only refers to the first occurrence but also includes recurrence.Therefore,myeloperoxidase is significant for the clinical evaluation and prognosis of stroke.This paper reviews the potential role played by myeloperoxidase in the development of vascular injury and secondary brain injury after stroke and explores the effects of inhibiting myeloperoxidase on stroke prognosis.This paper also analyzes the significance of myeloperoxidase etiology in the occurrence and development of stroke and discusses whether myeloperoxidase can be used as a target for the treatment and prediction of stroke.     

δ-Opioid receptor as a potential therapeutic target for ischemic stroke

Ischemic stroke is a global epidemic condition due to an inadequate supply of blood and oxygen to a specific area of brain either by arterial blockage or by narrowing of blood vessels.Despite having advancement in the use of thrombolytic and clot removal medicine,significant numbers of stroke patients are still left out without option for treatment.In this review,we summarize recent research work on the activation ofδ-opioid receptor as a strategy for treating ischemic stroke-caused neuronal injury.Moreover,as activation ofδ-opioid receptor by a non-peptidicδ-opioid receptor agonist also modulates the expression,maturation and processing of amyloid precursor protein andβ-secretase activity,the potential role of these effects on ischemic stroke caused dementia or Alzheimer’s disease are also discussed.     

Is alpha-synuclein pathology a target for treatment of neurodegenerative disorders?

Alpha-synuclein is the main constituent of intra-neuronal Lewy bodies, which are characteristic of Parkinson's disease, but aggregates are also found as axonal inclusions. Alpha-synuclein pathology is found together with beta-amyloid plaques and neurofibrillary tangles in Alzheimer's disease and other neurodegenerative disorders. In spite of the fact that the biological function of this synaptic protein is not known so far, there is an increasing body of evidence indicating an interaction with amyloid peptides, but also with tau-hyperphosphorylation. A high proportion of alpha-synuclein purified from Lewy bodies is phosphorylated on Ser129. There are still different opinions about the toxicity of the alpha-synuclein aggregates. Alpha-synuclein seems to influence different intracellular signaling pathways which are in direct relation to defense mechanisms against reactive oxygen species or apoptosis. It is obvious that overproduction of alpha-synuclein, but also different mutations, are inducing the formation of aggregates. Because of the possible link to neurodegeneration, different attempts have been made to counteract alpha-synuclein aggregation. An interesting approach is utilizing beta-synuclein, a biological factor, with an aminoacid sequence closely resembling that of alpha-synuclein. Proof of concept studies indicated that overexpression of beta-synuclein is able to counteract alpha-synuclein aggregation in a transgenic animal model, while also ameliorating functional deficits. As an alternative approach, the use of low molecular beta-synuclein N-terminal peptide derivatives has been considered. Several of these structures displayed clear neuroprotective activities in tissue culture models of neurodegeneration, including beta-amyloid toxicity. Therefore it has been speculated that these compounds might have a broad therapeutic efficacy in different neurodegenerative disorders. A proof of concept study in hAPP-transgenic animals resulted in a highly significant decrease in beta-amyloid plaque load, an increase in soluble beta-amyloid peptides and a decrease in insoluble forms. There was also significant improvement of cognitive deficits in this APP transgenic mouse model following intranasal but also peripheral treatment with three of these compounds. From this study it is concluded that the observed effects of the peptides derived from beta-synuclein N-terminus are depending on both, a direct interaction with aggregation of proteins, but also with stimulation of anti-apoptotic and anti-oxidative intracellular signaling pathways.     

Intra-axonal protein synthesis–a new target for neural repair?

Although initially argued to be a feature of immature neurons with incomplete polarization, there is clear evidence that neurons in the peripheral nervous system retain the capacity for intra-axonal protein synthe-sis well into adulthood. This localized protein synthesis has been shown to contribute to injury signaling and axon regeneration in peripheral nerves. Recent works point to potential for protein synthesis in axons of the vertebrate central nervous system. mRNAs and protein synthesis machinery have now been docu-mented in lamprey, mouse, and rat spinal cord axons. Intra-axonal protein synthesis appears to be activated in adult vertebrate spinal cord axons when they are regeneration-competent. Rat spinal cord axons regen-erating into a peripheral nerve graft contain mRNAs and markers of activated translational machinery. Indeed, levels of some growth-associated mRNAs in these spinal cord axons are comparable to the regen-erating sciatic nerve. Markers of active translation tend to decrease when these axons stop growing, but can be reactivated by a second axotomy. These emerging observations raise the possibility that mRNA transport into and translation within axons could be targeted to facilitate regeneration in both the peripheral and central nervous systems.