LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis.

Demyelinating diseases, such as multiple sclerosis, are characterized by the loss of the myelin sheath around neurons, owing to inflammation and gliosis in the central nervous system (CNS). Current treatments therefore target anti-inflammatory mechanisms to impede or slow disease progression. The identification of a means to enhance axon myelination would present new therapeutic approaches to inhibit and possibly reverse disease progression. Previously, LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) has been identified as an in vitro and in vivo negative regulator of oligodendrocyte differentiation and myelination. Here we show that loss of LINGO-1 function by Lingo1 gene knockout or by treatment with an antibody antagonist of LINGO-1 function leads to functional recovery from experimental autoimmune encephalomyelitis. This is reflected biologically by improved axonal integrity, as confirmed by magnetic resonance diffusion tensor imaging, and by newly formed myelin sheaths, as determined by electron microscopy. Antagonism of LINGO-1 or its pathway is therefore a promising approach for the treatment of demyelinating diseases of the CNS.

Prelimbic Cortical Stimulation with L-methionine Enhances Cognition through Hippocampal DNA Methylation and Neuroplasticity Mechanisms.

Declining global DNA methylation and cognitive impairment are reported to occur in the normal aging process. It is not known if DNA methylation plays a role in the efficacy of memory-enhancing therapies. In this study, aged animals were administered prelimbic cortical deep brain stimulation (PrL DBS) and/or L-methionine (MET) treatment. We found that PrL DBS and MET (MET-PrL DBS) co-administration resulted in hippocampal-dependent spatial memory enhancements in aged animals. Molecular data suggested MET-PrL DBS induced DNA methyltransferase DNMT3a-dependent methylation, robust synergistic upregulation of neuroplasticity-related genes, and simultaneous inhibition of the memory-suppressing gene calcineurin in the hippocampus. We further found that MET-PrL DBS also activated the PKA-CaMKIIα-BDNF pathway, increased hippocampal neurogenesis, and enhanced dopaminergic and serotonergic neurotransmission. We next inhibited the activity of DNA methyltransferase (DNMT) by RG108 infusion in the hippocampus of young animals to establish a causal relationship between DNMT activity and the effects of PrL DBS. Hippocampal DNMT inhibition in young animals was sufficient to recapitulate the behavioral deficits observed in aged animals and abolished the memory-enhancing and molecular effects of PrL DBS. Our findings implicate hippocampal DNMT as a therapeutic target for PrL DBS and pave way for the potential use of non-invasive neuromodulation modalities against dementia.

Prelimbic Cortical Stimulation Improves Spatial Memory Through Distinct Patterns of Hippocampal Gene Expression in Aged Rats.

Dementia poses major health challenges worldwide, yet current treatments are faced with issues of efficacy and toxicity. Deep brain stimulation (DBS) is a promising non-pharmacological treatment for dementia, but most DBS studies use young healthy animals, which may not be aetiologically relevant. In this study, we used an aged rat model in which cognitive decline occurs through a natural ageing process. We used a Morris water maze (MWM) to determine the effects of prelimbic cortex (PrL) DBS on memory in aged rats. To investigate the underlying mechanisms of the effects of DBS, we carried out microarray, quantitative PCR analysis, and mass spectrometry to detect gene expression and neurotransmitter changes in the hippocampus. We showed PrL DBS improved the performance in MWM, with related distinct patterns of gene expression involving G protein-coupled receptor pathways. We further found neurotransmitter changes in the dorsal hippocampus, which corroborated and extended the microarray findings. Our results suggest that non-neurogenesis pathways play roles in the effects of DBS. Further studies are needed to investigate the effects of DBS on memory beyond neurogenesis and to consider the highlighted pathways suggested by our data.

Somatosensory-evoked potentials as an indicator for the extent of ultrastructural damage of the spinal cord after chronic compressive injuries in a rat model.

OBJECTIVE: Somatosensory-evoked potentials (SEPs) were found to correlate well with the disability and postoperative recovery in patients with cervical spondylotic myelopathy. Yet the exact pathophysiology behind it remains to be elucidated. This study aims to characterise the ultrastructural changes of a chronically compressive spinal cord with various SEP responses in a rat model. METHODS: A total of 15 rats were used with surgical implantation of a water-absorbing polymer sheet into the cervical spinal canal on the postero-lateral side, which expanded over time to induce chronic compression in the cord. At postoperative 6 months, the functional integrity of the cords was recorded by SEP responses by comparing injured and non-injured sides, and the ultrastructural integrity was assessed by 7-T magnetic resonance (MR) diffusion imaging, contrast-enhanced micro-computed tomography (µCT) and histological evaluations. RESULTS: Six rats showed unchanged SEP, and the other nine showed decreased amplitude only (n=5) or delayed latency (n=4). The circulation insults of the cords were found among all the rats, showing central canal enlargement, intra-tissue bleeding or increased blood vessels in the central grey matter. Ultrastructural damage was noted in the rats with changed SEP responses, which was suggested by lower fractional anisotropy and higher contrast intensity radiologically and echoed by less myelin stain and cavitation changes histologically. In the animals with delayed latency, the cord showed significant loss of motoneurons as well as gross appearance distortion. CONCLUSIONS: The categorised SEP responses by amplitude and latency could be an indicator for the extent of ultrastructural damage of the spinal cord after chronic compressive injuries. SIGNIFICANCE: The findings built a solid foundation for SEP application in clinical diagnosis and prognostication of spinal cord injuries.

C-reactive protein promotes cardiac fibrosis and inflammation in angiotensin II-induced hypertensive cardiac disease.

C-reactive protein (CRP) is a risk factor or biomarker for cardiovascular diseases, including hypertension. The present study investigated the functional importance of human CRP in hypertensive cardiac remodeling by a chronic infusion of angiotensin II (Ang II) into mice that express human CRP. Compared with the wild-type mice, although Ang II infusion caused an equally high systolic blood pressure, levels of human CRP were further elevated, and cardiac remodeling was markedly exacerbated in mice that express human CRP, resulting in a significant reduction in the left ventricular ejection fraction and fractional shortening and an increase in cardiac fibrosis (collagen I and III and alpha-smooth muscle actin) and inflammation (interleukin 1beta and tumor necrosis factor-alpha). The enhancement in cardiac remodeling in mice that express human CRP was associated with further upregulation of the Ang II type I receptor and transforming growth factor-beta1 and overactivation of both transforming growth factor-beta/Smad and nuclear factor-kappaB signaling pathways. Furthermore, in vitro studies in cardiac fibroblasts revealed that CRP alone was able to significantly induce expression of the Ang II type I receptor, collagen I/III, and alpha-smooth muscle actin, as well as proinflammation cytokines (interleukin 1beta and tumor necrosis factor-alpha), which was further enhanced by addition of Ang II. In conclusion, CRP is not only a biomarker but also a mediator in Ang II-mediated cardiac remodeling. Enhanced upregulation of the Ang II type I receptor and activation of the transforming growth factor-beta/Smad and nuclear factor-kappaB signaling pathways may be the mechanisms by which CRP promotes cardiac fibrosis and inflammation under high Ang II conditions.

A free-breathing non-contrast-enhanced pulmonary magnetic resonance angiography at 3 Tesla.

BACKGROUND: The breathhold contrast-enhanced three-dimensional magnetic resonance angiography (MRA) using T1-weighted gradient-echo imaging sequence is the standard technique for MRA of the thorax. However, this technique is not desirable for certain patients with respiratory insufficiency, serious renal impairment, or allergy to contrast agents. The objective of this study was to optimize and evaluate a non-contrast-enhanced free-breathing pulmonary MRA protocol at 3 Tesla. METHODS: The time-of-flight protocol was based on a two-dimensional T1-weighted turbo field echo sequence with slice-selective inversion recovery and magnetization transfer preparation together with respiratory navigator gating, cardiac gating, and parallel imaging. Optimal values for time of inversion delay, flip angle and slice thickness were experimentally determined and used for all subjects. RESULTS: Excellent pulmonary MRA images, in which the 7th order branches of pulmonary arteries could be reliably identified, were obtained in the 12 free-breathing healthy volunteers. TI of approximately 300 ms provides the best suppression of background thoracic and cardiac muscles and effective inflow enhancement. With increasing flip angle, the pulmonary vessels gradually brightened and exhibited optimal contrast at 20 degrees-30 degrees. The 2 mm slice thickness and 0.5 mm slice overlap is suitable for visualization of the peripheral pulmonary vessel. CONCLUSIONS: The MRA protocol at 3 Tesla may have clinical significance for pulmonary vascular imaging in patients who are not available for contrast-enhanced 3D MRA and CT angiography examination or are unable to sustain a long breath-hold.