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Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis
In Parkinson’s disease (PD) there is a selective degeneration of neuromelanin-containing neurons, especially substantia nigra dopaminergic neurons. In humans, neuromelanin accumulates with age, the latter being the main risk factor for PD. The contribution of neuromelanin to PD pathogenesis remains unknown because, unlike humans, common laboratory animals lack neuromelanin. Synthesis of peripheral melanins is mediated by tyrosinase, an enzyme also present at low levels in the brain. Here we report that overexpression of human tyrosinase in rat substantia nigra results in age-dependent production of human-like neuromelanin within nigral dopaminergic neurons, up to levels reached in elderly humans. In these animals, intracellular neuromelanin accumulation above a specific threshold is associated to an age-dependent PD phenotype, including hypokinesia, Lewy body-like formation and nigrostriatal neurodegeneration. Enhancing lysosomal proteostasis reduces intracellular neuromelanin and prevents neurodegeneration in tyrosinase-overexpressing animals. Our results suggest that intracellular neuromelanin levels may set the threshold for the initiation of PD.
It is unclear if neuromelanin plays a role in Parkinson’s disease pathogenesis since common laboratory animals lack this pigment. Authors show here that overexpression of human tyrosinase in the substantia nigra of rats resulted in an age-dependent production of human-like neuromelanin within nigral dopaminergic neurons and is associated with a Parkinson’s disease phenotype when allowed to accumulate above a specific threshold.
Journal Article
Animal Models for Microbiome Research
The surface of the human body and its mucous membranes are heavily colonized by microorganisms. Our understanding of the contributions that complex microbial communities make to health and disease is advancing rapidly. Most microbiome research to date has focused on the mouse as a model organism for delineating the mechanisms that shape the assembly and dynamic operations of microbial communities. However, the mouse is not a perfect surrogate for studying different aspects of the microbiome and how it responds to various environmental and host stimuli, and as a result, researchers have been conducting microbiome studies in other animals.
To examine the different animal models researchers employ in microbiome studies and to better understand the strengths and weaknesses of each of these model organisms as they relate to human and nonhuman health and disease, the Roundtable on Science and Welfare in Laboratory Animal Use of the National Academies of Sciences, Engineering, and Medicine convened a workshop in December 2016. The workshop participants explored how to improve the depth and breadth of analysis of microbial communities using various model organisms, the challenges of standardization and biological variability that are inherent in gnotobiotic animal-based research, the predictability and translatability of preclinical studies to humans, and strategies for expanding the infrastructure and tools for conducting studies in these types of models. This publication summarizes the presentations and discussions from the workshop.
eBook
PACAP38 and PAC1 receptor blockade: a new target for headache?
Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) is a widely distributed neuropeptide involved in neuroprotection, neurodevelopment, nociception and inflammation. Moreover, PACAP38 is a potent inducer of migraine-like attacks, but the mechanism behind this has not been fully elucidated.Migraine is a neurovascular disorder, recognized as the second most disabling disease. Nevertheless, the antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor are the only prophylactic treatment developed specifically for migraine. These antibodies have displayed positive results in clinical trials, but are not effective for all patients; therefore, new pharmacological targets need to be identified.Due to the ability of PACAP38 to induce migraine-like attacks, its location in structures previously associated with migraine pathophysiology and the 100-fold selectivity for the PAC1 receptor when compared to VIP, new attention has been drawn to this pathway and its potential role as a novel target for migraine treatment. In accordance with this, antibodies against PACAP38 (ALD 1910) and PAC1 receptor (AMG 301) are being developed, with AMG 301 already in Phase II clinical trials. No results have been published so far, but in preclinical studies, AMG 301 has shown responses comparable to those observed with triptans. If these antibodies prove to be effective for the treatment of migraine, several considerations should be addressed, for instance, the potential side effects of long-term blockade of the PACAP (receptor) pathway. Moreover, it is important to investigate whether these antibodies will indeed represent a therapeutic advantage for the patients that do not respond the CGRP (receptor)-antibodies.In conclusion, the data presented in this review indicate that PACAP38 and PAC1 receptor blockade are promising antimigraine therapies, but results from clinical trials are needed in order to confirm their efficacy and side effect profile.
Journal Article
Insulinlike Growth Factor (IGF)-1 Administration Ameliorates Disease Manifestations in a Mouse Model of Spinal and Bulbar Muscular Atrophy
Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by polyglutamine expansion in the androgen receptor. Patients develop slowly progressive proximal muscle weakness, muscle atrophy and fasciculations. Affected individuals often show gynecomastia, testicular atrophy and reduced fertility as a result of mild androgen insensitivity. No effective disease-modifying therapy is currently available for this disease. Our recent studies have demonstrated that insulinlike growth factor (IGF)-1 reduces the mutant androgen receptor toxicity through activation of Akt
in vitro
, and spinal and bulbar muscular atrophy transgenic mice that also overexpress a noncirculating muscle isoform of IGF-1 have a less severe phenotype. Here we sought to establish the efficacy of daily intraperitoneal injections of mecasermin rinfabate, recombinant human IGF-1 and IGF-1 binding protein 3, in a transgenic mouse model expressing the mutant androgen receptor with an expanded 97 glutamine tract. The study was done in a controlled, randomized, blinded fashion, and, to reflect the clinical settings, the injections were started after the onset of disease manifestations. The treatment resulted in increased Akt phosphorylation and reduced mutant androgen receptor aggregation in muscle. In comparison to vehicle-treated controls, IGF-1–treated transgenic mice showed improved motor performance, attenuated weight loss and increased survival. Our results suggest that peripheral tissue can be targeted to improve the spinal and bulbar muscular atrophy phenotype and indicate that IGF-1 warrants further investigation in clinical trials as a potential treatment for this disease.
Journal Article
Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis
Blood-supply boost in ischaemia
The cellular oxygen-sensing enyzme PHD2 uses oxygen to degrade hypoxia-inducible factor 1α. Using a mouse model of limb ischaemia, Takeda
et al
. link oxygen sensing through PHD2 to macrophage phenotype and arteriogenesis. They show that myeloid-cell-specific PHD2 haplodeficiency results in improved arteriogenesis after ischaemia owing to hyperactivation of NFκB signalling in the macrophages and the promotion of an M2-like repair phenotype. This suggests that PHD2 inhibition might promote collateral vascularization in patients who are at risk of limb or heart ischaemia.
PHD2 serves as an oxygen sensor that rescues blood supply by regulating vessel formation and shape in case of oxygen shortage
1
,
2
,
3
,
4
,
5
. However, it is unknown whether PHD2 can influence arteriogenesis. Here we studied the role of PHD2 in collateral artery growth by using hindlimb ischaemia as a model, a process that compensates for the lack of blood flow in case of major arterial occlusion
6
,
7
,
8
. We show that
Phd2
(also known as
Egln1
) haplodeficient (
Phd2
+/−
) mice displayed preformed collateral arteries that preserved limb perfusion and prevented tissue necrosis in ischaemia. Improved arteriogenesis in
Phd2
+/−
mice was due to an expansion of tissue-resident, M2-like macrophages
9
,
10
and their increased release of arteriogenic factors, leading to enhanced smooth muscle cell (SMC) recruitment and growth. Both chronic and acute deletion of one
Phd2
allele in macrophages was sufficient to skew their polarization towards a pro-arteriogenic phenotype. Mechanistically, collateral vessel preconditioning relied on the activation of canonical NF-κB pathway in
Phd2
+/−
macrophages. These results unravel how PHD2 regulates arteriogenesis and artery homeostasis by controlling a specific differentiation state in macrophages and suggest new treatment options for ischaemic disorders.
Journal Article
Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques
In 2012, a novel betacoronavirus, designated Middle East respiratory syndrome coronavirus or MERS-CoV and associated with severe respiratory disease in humans, emerged in the Arabian Peninsula. To date, 108 human cases have been reported, including cases of human-to-human transmission. The availability of an animal disease model is essential for understanding pathogenesis and developing effective countermeasures. Upon a combination of intratracheal, ocular, oral, and intranasal inoculation with 7 × 10 ⁶ 50% tissue culture infectious dose of the MERS-CoV isolate HCoV-EMC/2012, rhesus macaques developed a transient lower respiratory tract infection. Clinical signs, virus shedding, virus replication in respiratory tissues, gene expression, and cytokine and chemokine profiles peaked early in infection and decreased over time. MERS-CoV caused a multifocal, mild to marked interstitial pneumonia, with virus replication occurring mainly in alveolar pneumocytes. This tropism of MERS-CoV for the lower respiratory tract may explain the severity of the disease observed in humans and the, up to now, limited human-to-human transmission.
Journal Article
Osmolality of enteral formula and severity of experimental necrotizing enterocolitis
Purpose
Administration of hyperosmolar formula is regarded as a risk factor for the development of necrotizing enterocolitis (NEC). However, there are limited number of reports about the relationship between formula osmolality and NEC. The aim of this study is to evaluate the effects of formula concentration in an experimental model of NEC.
Methods
We studied experimental NEC in C57BL/6 mice. NEC was induced by giving hypoxia, gavage administration of lipopolysaccharide and gavage formula feeding from postnatal day 5–9. We used two types of formula: (1) hyperosmolar formula (HF): 15 g Similac + 75 ml Esbilac (849 mOsm/kg); (2) diluted formula (DF): dilute hyperosmolar formula with an equal amount of water (325 mOsm/kg). Controls were fed by the mother. On postnatal day 9, the ileum was harvested and evaluated for severity of mucosal injury (hematoxylin/eosin staining) and inflammation (PCR for IL6 and TNFα mRNA expression).
Results
The incidence of NEC was same in both HF and DF (80%). The intestinal inflammatory response was similar between HF and DF (IL6:
p
= 0.26, TNFα:
p
= 0.69).
Conclusions
This study indicates the osmolality of enteral formula does not affect incidence of experimental NEC. This experimental study provides new insights into the relationship between formula feeding and NEC.
Journal Article
Rivaroxaban improves vascular response in LPS-induced acute inflammation in experimental models
Rivaroxaban (RVX) was suggested to possess anti-inflammatory and vascular tone modulatory effects. The goal of this study was to investigate whether RVX impacts lipopolysaccharide (LPS)-induced acute vascular inflammatory response. Male rats were treated with 5 mg/kg RVX (oral gavage) followed by 10 mg/kg LPS i.p injection. Circulating levels of IL-6, MCP-1, VCAM-1, and ICAM-1 were measured in plasma 6 and 24 hours after LPS injection, while isolated aorta was used for gene expression analysis, immunohistochemistry, and vascular tone evaluation. RVX pre-treatment significantly reduced LPS mediated increase after 6h and 24h for IL-6 (4.4±2.2 and 2.8±1.7 fold), MCP-1 (1.4±1.5 and 1.3±1.4 fold) VCAM-1 (1.8±2.0 and 1.7±2.1 fold). A similar trend was observed in the aorta for iNOS (5.5±3.3 and 3.3±1.9 folds reduction, P<0.01 and P<0.001, respectively), VCAM-1 (1.3±1.2 and 1.4±1.3 fold reduction, P<0.05), and MCP-1 (3.9±2.2 and 1.9±1.6 fold reduction, P<0.01). Moreover, RVX pre-treatment, improved LPS-induced PE contractile dysfunction in aortic rings (Control
vs
LPS, Emax reduction = 35.4 and 31.19%, P<0.001; Control
vs
LPS+RVX, Emax reduction = 10.83 and 11.48%, P>0.05, respectively), resulting in 24.5% and 19.7% change in maximal constriction in LPS and LPS+RVX respectively. These data indicate that RVX pre-treatment attenuates LPS-induced acute vascular inflammation and contractile dysfunction.
Journal Article
Successful vaccines for naturally occurring protozoal diseases of animals should guide human vaccine research. A review of protozoal vaccines and their designs
Effective vaccines are available for many protozoal diseases of animals, including vaccines for zoonotic pathogens and for several species of vector-transmitted apicomplexan haemoparasites. In comparison with human diseases, vaccine development for animals has practical advantages such as the ability to perform experiments in the natural host, the option to manufacture some vaccines in vivo, and lower safety requirements. Although it is proper for human vaccines to be held to higher standards, the enduring lack of vaccines for human protozoal diseases is difficult to reconcile with the comparatively immense amount of research funding. Common tactical problems of human protozoal vaccine research include reliance upon adapted rather than natural animal disease models, and an overwhelming emphasis on novel approaches that are usually attempted in replacement of rather than for improvement upon the types of designs used in effective veterinary vaccines. Currently, all effective protozoal vaccines for animals are predicated upon the ability to grow protozoal organisms. Because human protozoal vaccines need to be as effective as animal vaccines, researchers should benefit from a comparison of existing veterinary products and leading experimental vaccine designs. With this in mind, protozoal vaccines are here reviewed.
Journal Article