Comparison of results between chitosan hollow tube and autologous nerve graft in reconstruction of peripheral nerve defect: An experimental study.

OBJECT: This study evaluated a chitosan tube for regeneration of the injured peripheral nerve in a rodent transected sciatic nerve model in comparison to autologous nerve graft repair. METHODS: Chitosan hollow tube was used to bridge a 10-mm gap between the proximal and distal ends in 11 rats. In the control group, an end-to-end coaptation of 10-mm long autologous nerve graft was performed in 10 rats for nerve reconstruction. RESULTS: SFI showed an insignificant advantage to the autologous group both at 30 days (P = 0.177) and at 90 days post procedure (P = 0.486). Somato-sensory evoked potentials (SSEP) and compound muscle action potentials (CMAP) tests showed similar results between chitosan tube (group 1) and autologous (group 2) groups with no statistically significant differences. Both groups presented the same pattern of recovery with 45% in group 1 and 44% in group 2 (P = 0.96) showing SSEP activity at 30 days. At 90 days most rats showed SSEP activity (91% vs.80% respectively, P = 0.46). The CMAP also demonstrated no statistically significant differences in latency (1.39 ms in group 1 vs. 1.63 ms in group 2; P = 0.48) and amplitude (6.28 mv vs. 6.43 mv respectively; P = 0.8). Ultrasonography demonstrated tissue growth inside the chitosan tube. Gastrocnemius muscle weight showed no statistically significant difference. Histomorphometry of the distal sciatic nerve, 90 days post reconstructive procedure, showed similar number of myelinated fibers and size parameters in both groups (P ≥ 0.05). CONCLUSIONS: Chitosan hollow tube used for peripheral nerve reconstruction of rat sciatic nerve showed similar results in comparison to autologous nerve grafting. © 2015 Wiley Periodicals, Inc. Microsurgery 36:664-671, 2016.

Lowering mutant huntingtin by small molecules relieves Huntington's disease symptoms and progression.

Huntington's disease (HD) is an incurable inherited disorder caused by a repeated expansion of glutamines in the huntingtin gene (Htt). The mutant protein causes neuronal degeneration leading to severe motor and psychological symptoms. Selective downregulation of the mutant Htt gene expression is considered the most promising therapeutic approach for HD. We report the identification of small molecule inhibitors of Spt5-Pol II, SPI-24 and SPI-77, which selectively lower mutant Htt mRNA and protein levels in HD cells. In the BACHD mouse model, their direct delivery to the striatum diminished mutant Htt levels, ameliorated mitochondrial dysfunction, restored BDNF expression, and improved motor and anxiety-like phenotypes. Pharmacokinetic studies revealed that these SPIs pass the blood-brain-barrier. Prolonged subcutaneous injection or oral administration to early-stage mice significantly delayed disease deterioration. SPI-24 long-term treatment had no side effects or global changes in gene expression. Thus, lowering mutant Htt levels by small molecules can be an effective therapeutic strategy for HD.

Silc1 long noncoding RNA is an immediate-early gene promoting efficient memory formation.

Long noncoding RNAs (lncRNAs) are expressed in many brain circuits and types of neurons; nevertheless, their functional significance for normal brain functions remains elusive. Here, we study the functions in the central nervous system of Silc1, an lncRNA we have shown previously to be important for neuronal regeneration in the peripheral nervous system. We found that Silc1 is rapidly and strongly induced in the hippocampus upon exposure to novelty and is required for efficient spatial learning. Silc1 production is important for induction of Sox11 (its cis-regulated target gene) throughout the CA1-CA3 regions and proper expression of key Sox11 target genes. Consistent with its role in neuronal plasticity, Silc1 levels decline during aging and in models of Alzheimer's disease. Overall, we describe a plasticity pathway in which Silc1 acts as an immediate-early gene to activate Sox11 and induce a neuronal growth-associated transcriptional program important for learning.

Mitochondrial function and brain Metabolic Score (BMS) in ischemic Stroke: Evaluation of "neuroprotectants" safety and efficacy.

The initial and significant event developed in ischemic stroke is the sudden decrease in blood flow and oxygen supply to brain tissue, leading to dysfunction of the mitochondria. Many attempts were and are being made to develop new drugs and treatments that will save the ischemic brain, but the efficacy is not optimal and in many patients, irreversible damage to the brain will persist. We review a unique approach to evaluate mitochondrial function and microcirculatory hemodynamic in real time in vivo. Three out of four monitored physiological parameters are integrated into a new Brain Metabolic Score (BMS) calculated in real time and is correlated to Brain Oxygen Balance. The technology was adapted to various experimental as well as clinical situations for monitoring the brain in real time. The developed protocols could be used in testing the efficacy and safety of new drugs in experimental animals. Few models of brain monitoring during partial or complete ischemia were developed and used in naive animals or under brain activation protocols. It was found that mitochondrial function/dysfunction is the major and dominant parameter affecting the calculated Brain Metabolic Score. Using our monitoring system and protocols will provide direct information regarding the ability of the tested brain to provide enough oxygen consumed by the mitochondria in the "resting" or in the "activated" brain in vivo and in real-time. Preliminary studies, indicated that testing the efficacy and safety of new neuroprotectant drugs provided significant results to the R&D studies of ischemic stroke related to mitochondrial function.

Pathological and clinical aspects of alpha/beta synuclein in Parkinson's disease and related disorders.

Parkinson's disease (PD) and related synucleinopathies are characterized by extensive neuronal cell loss, which is potentially triggered by α-synuclein misfolding and aggregation. Therefore it is reasonable to suggest that treatments targeting α-synuclein could reduce its levels and toxicity, rescue neuronal cells and halt the neurodegeneration process. Several approaches to decrease α-synuclein levels were employed thus far, mainly by using ß-synuclein, another protein from the same family, or immunotherapies. These treatments demonstrated some positive results in preclinical studies, which may pave the road to the development of new promising disease-modifying therapies (DMTs). This approach should be further examined in preclinical and clinical settings, together with a clear process in order to advance candidates, enable the ability to define when there are target engagements and to detect what is a meaningful pharmacological response, and how it will be translated in clinical efficacy.

Can the "brain-sparing effect" be detected in a small-animal model?

BACKGROUND: Under O(2) imbalance in the body, blood redistribution occurs between more vital organs and less vital organs. This response is defined as the "brain-sparing effect". The study's aim was to develop a new rat model for simultaneous real-time monitoring of tissue viability in a highly vital organ, the brain, and a less vital organ, the small intestine, under various metabolic perturbations and emergency-like situations. MATERIAL/METHODS: The cerebral cortex and intestinal serosa were exposed in anesthetized rats and a multi-site multi-parametric (MSMP) monitoring system was connected to both. Tissue blood flow (TBF) was monitored using laser Doppler flowmetry and mitochondrial function by NADH fluorometry. The perturbations performed were anoxia (30 sec) and 20 minutes of hypoxia, hypercapnia, or hyperoxia. RESULTS: Under oxygen deficiency, cerebral blood flow (CBF) increased (315+/-53% in anoxia and 140+/-12% in hypoxia), whereas intestinal blood flow decreased (60+/-11% in anoxia and 56+/-13% in hypoxia). Mitochondrial NADH significantly increased in both organs (119+/-2.8% and 151+/-14% in the brain and intestine, respectively). Under hyperoxia, NADH was oxidized in both organs (up to 9% change). Hypercapnia led to an increase in CBF (143+/-11%) and oxidation of mitochondrial NADH (by 10%), with no significant changes in the intestine. CONCLUSIONS: The two organs respond significantly differently to lack of O(2) by activating the sympathetic nervous system. Monitoring less vital organs may indicate an early response to emergency situations. Therefore, a less vital organ could be used as a surrogate organ to be monitored in order to spare the brain.