Free ubiquitin: a novel therapeutic target for neurodegenerative diseases

正Neurodegenerative diseases are widespread and the increasing number of patients with these diseases can no longer be ignored. Dementia is a symptom of many neurodegenerative diseases, and Alzheimer's disease(AD), which is associated with memory and learning disabilities, accounts for approximately 60 to 80% of all dementia cases(Wyss-Coray, 2016).     

Tissue transglutaminase: a novel therapeutic target in cerebral amyloid angiopathy

Accumulation of amyloid-β (Aβ) in brain vessel walls, known as cerebral amyloid angiopathy (CAA), plays a key role in Alzheimer's disease pathogenesis. CAA might result from impaired transport of Aβ out of the brain. Although the mechanisms underlying reduced Aβ transport are largely unknown, thickening of basement membrane extracellular matrix (ECM) is likely involved. Tissue transglutaminase (tTG) is an enzyme capable of modulating the ECM by covalently cross-linking ECM proteins. Recently, our group found that tTG and its cross-linking activity are associated with CAA pathology, suggesting a role for tTG in ECM modulation in CAA. Therefore, inhibition of tTG activity might be a promising novel therapeutic target to counteract CAA.     

Soluble epoxide hydrolase: a novel therapeutic target in stroke.

The P450 eicosanoids epoxyeicosatrienoic acids (EETs) are produced in brain and perform important biological functions, including protection from ischemic injury. The beneficial effect of EETs, however, is limited by their metabolism via soluble epoxide hydrolase (sEH). We tested the hypothesis that sEH inhibition is protective against ischemic brain damage in vivo by a mechanism linked to enhanced cerebral blood flow (CBF). We determined expression and distribution of sEH immunoreactivity (IR) in brain, and examined the effect of sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE) on CBF and infarct size after experimental stroke in mice. Mice were administered a single intraperitoneal injection of AUDA-BE (10 mg/kg) or vehicle at 30 mins before 2-h middle cerebral artery occlusion (MCAO) or at reperfusion, in the presence and absence of P450 epoxygenase inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH). Immunoreactivity for sEH was detected in vascular and non-vascular brain compartments, with predominant expression in neuronal cell bodies and processes. 12-(3-Adamantan-1-yl-ureido)-dodecanoic acid butyl ester was detected in plasma and brain for up to 24 h after intraperitoneal injection, which was associated with inhibition of sEH activity in brain tissue. Finally, AUDA-BE significantly reduced infarct size at 24 h after MCAO, which was prevented by MS-PPOH. However, regional CBF rates measured by iodoantipyrine (IAP) autoradiography at end ischemia revealed no differences between AUDA-BE- and vehicle-treated mice. The findings suggest that sEH inhibition is protective against ischemic injury by non-vascular mechanisms, and that sEH may serve as a therapeutic target in stroke.     

A novel therapeutic target for peripheral nerve injury-related diseases: aminoacyl-tRNA synthetases

Aminoacyl-t RNA synthetases(Amino ARSs) are essential enzymes that perform the first step of protein synthesis. Beyond their original roles, Amino ARSs possess non-canonical functions, such as cell cycle regulation and signal transduction. Therefore, Amino ARSs represent a powerful pharmaceutical target if their non-canonical functions can be controlled. Using Amino ARSs-specific primers, we screened m RNA expression in the spinal cord dorsal horn of rats with peripheral nerve injury created by sciatic nerve axotomy. Of 20 Amino ARSs, we found that phenylalanyl-t RNA synthetase beta chain(FARSB), isoleucyl-t RNA synthetase(IARS) and methionyl-t RNA synthetase(MARS) m RNA expression was increased in spinal dorsal horn neurons on the injured side, but not in glial cells. These findings suggest the possibility that FARSB, IARS and MARS, as a neurotransmitter, may transfer abnormal sensory signals after peripheral nerve damage and become a new target for drug treatment.     

The serotonin-7 receptor as a novel therapeutic target

Issue: Blockade of 5-HT7 receptors may be a novel therapeutic approach for achieving antidepressant and memory-enhancing actions.     

Invited Article: Threats to physician autonomy in a performance-based reimbursement system

Physician autonomy is currently threatened by the external application of pay for performance standards and required conformity to practice guidelines. This phenomenon is being driven by concerns over the economic viability of increasing per capita health care expenditures without a concomitant rise in favorable health outcomes and by the unjustified marked variations among physicians' practice patterns. Proponents contend that altering the reimbursement system to encourage physicians to make choices based upon the best available evidence would be one way to ensure better outcomes per health care dollar spent. Although physician autonomy is most easily justified when decisions are made by appealing to the best available evidence, incentivizing decision-making risks sacrificing physician autonomy to political and social forces if the limitations of evidence-based medicine are not respected. Any reimbursement system designed to encourage physicians to utilize the best available evidence by providing financial incentives must recognize physicians who try to play to the numbers as well as physicians who refuse to follow the best available evidence if doing so would conflict with good medicine or patient preferences. By designing, promulgating, and updating evidence-based clinical practice guidelines, medical specialty societies can limit threats to physician autonomy while improving medical practice.     

Autonomic ganglia, acetylcholine receptor antibodies, and autoimmune ganglionopathy

Nicotinic acetylcholine receptors (AChR) are ligand-gated cation channels that are present throughout the nervous system. The ganglionic (alpha3-type) neuronal AChR mediates fast synaptic transmission in sympathetic, parasympathetic and enteric autonomic ganglia. Autonomic ganglia are an important site of neural integration and regulation of autonomic reflexes. Impaired cholinergic ganglionic synaptic transmission is one important cause of autonomic failure. Ganglionic AChR antibodies are found in many patients with autoimmune autonomic ganglionopathy (AAG). These antibodies recognize the alpha3 subunit of the ganglionic AChR, and thus do not bind non-specifically to other nicotinic AChR. Patients with high levels of ganglionic AChR antibodies typically present with rapid onset of severe autonomic failure, with orthostatic hypotension, gastrointestinal dysmotility, anhidrosis, bladder dysfunction and sicca symptoms. Impaired pupillary light reflex is often seen. Like myasthenia gravis, AAG is an antibody-mediated neurological disorder. Antibodies from patients with AAG inhibit ganglionic AChR currents and impair transmission in autonomic ganglia. An animal model of AAG in the rabbit recapitulates the important clinical features of the human disease and provides additional evidence that AAG is an antibody-mediated disorder caused by impairment of synaptic transmission in autonomic ganglia.     

Filamentous bacteriophage as a novel therapeutic tool for Alzheimer's disease treatment

Antibodies towards the N-terminal region of the amyloid-beta peptide (AbetaP) bind to Abeta fibrils, leading to their disaggregation. We developed an immunization procedure using filamentous phages displaying the only four amino acids EFRH encompassing amino acids 3-6 of the 42 residues of AbetaP, found to be the main regulatory site for Abeta formation. Phages displaying EFRH epitope are effective in eliciting humoral response against AbetaP which, in turn, relieves amyloid burden in brains of amyloid-beta protein precursor transgenic mice, improving their ability to perform cognitive tasks. In order to overcome the low permeability of the blood brain barrier for targeting 'anti-aggregating' monoclonal antibodies (mAbs) to Abeta plaques in the brain, we applied antibody engineering methods to minimize the size of mAbs while maintaining their biological activity. Single-chain antibodies displayed on the surface of filamentous phage showed the ability to enter the central nervous system (CNS). The genetically engineered filamentous bacteriophage proved to be an efficient, nontoxic viral delivery vector to the brain, offering an obvious advantage over other mammalian vectors. The feasibility of these novel strategies for production and targeting of anti-aggregating antibodies against Abeta plaques to disease affected regions in the CNS may have clinical potential for treatment of Alzheimer's disease.     

Oxidized low-density lipoprotein receptor 1: a novel potential therapeutic target for intracerebral hemorrhage

Oxidized low-density lipoprotein receptor 1(OLR1)is upregulated in neurons and participates in hypertension-induced neuronal apoptosis.OLR1 deletion exerts protective effects on cerebral damage induced by hypertensive-induced stroke.Therefore,OLR1 is likely involved in the progress of intracerebral hemorrhage.In this study,we examined the potential role of OLR1 in intracerebral hemorrhage using a rat model.OLR1 small interfering RNA(10μL;50 pmol/μL)was injected into the right basal ganglia to knock down OLR1.Twenty-four hours later,0.5 U collagenase type VII was injected to induce intracerebral hemorrhage.We found that knockdown of OLR1 attenuated neurological behavior impairment in rats with intracerebral hemorrhage and reduced hematoma,neuron loss,inflammatory reaction,and oxidative stress in rat brain tissue.We also found that silencing of OLR1 suppressed ferroptosis induced by intracerebral hemorrhage and the p38 signaling pathway.Therefore,silencing OLR1 exhibits protective effects against secondary injury of intracerebral hemorrhage.These findings suggest that OLR1 may be a novel potential therapeutic target for intracerebral hemorrhage.     

Walking: an important therapeutic tool

This column discusses the concepts of an integrated psychotherapeutic approach to patient care and explores some of the underlying principles that make it beneficial.     

Autophagy: novel insights into therapeutic target of electroacupuncture against cerebral ischemia/reperfusion injury

Electroacupuncture is known as an effective adjuvant therapy in ischemic cerebrovascular disease. However, its underlying mechanisms remain unclear. Studies suggest that autophagy, which is essential for cell survival and cell death, is involved in cerebral ischemia reperfusion injury and might be modulate by electroacupuncture therapy in key ways. This paper aims to provide novel insights into a therapeutic target of electroacupuncture against cerebral ischemia/reperfusion injury from the perspective of autophagy. Here we review recent studies on electroacupuncture regulation of autophagy-related markers such as UNC-51-like kinase-1 complex, Beclin1, microtubule-associated protein-1 light chain 3, p62, and autophagosomes for treating cerebral ischemia/reperfusion injury. The results of these studies show that electroacupuncture may affect the initiation of autophagy, vesicle nucleation, expansion and maturation of autophagosomes, as well as fusion and degradation of autophagolysosomes. Moreover, studies indicate that electroacupuncture probably modulates autophagy by activating the mammalian target of the rapamycin signaling pathway.This review thus indicates that autophagy is a therapeutic target of electroacupuncture treatment against ischemic cerebrovascular diseases.     

Proinflammatory mediators and migraine pathogenesis: moving towards CGRP as a target for a novel therapeutic class

Migraine is a complex neurological disorder in which genetic and environmental factors interact. At present, frontline therapies in migraine's acute treatment include the use of NSAIDS and triptans. Restrictions in the use of frontline drugs for migraine treatment and evidence concerning CGRP's key role led research towards new pathways involved in migraine pathophysiology. CGRP is a strong vasodilatory neuropeptide released from activated trigeminal sensory nerves. The development of CGRP antagonists has also been driven by the fact that triptans are vasoconstrictive and cannot be used in patients with vascular risk factors. BIBN4096 (olcegepant) is the first CGRP antagonist for the treatment of migraine which has been tested in clinical trials, but its principal limitation is that BIBN4096 presents low oral bioavailability and has only been tested through intravenous formulation. The first oral nonpeptide CGRP antagonist, MK-0974 (telcagepant), has recently been shown to be highly effective in the treatment of migraine attacks. This development can be considered the most important pharmacological breakthrough for migraine treatment since the introduction of sumatriptan in the early 1990s. These results are important since they confirm the current pathophysiological concept of migraine. The future introduction of CGRP antagonists in clinical practice could represent a progress for migraine therapy.