(1) There has been no consensus on the role of autophagy in the onset of neurodegenerative diseases, but autophagy is considered one of important issues in the field of neuroscience.
(2) This review article summarizes the distinct steps of the autophagic process, correlates its orderly function with nerve cell homeostasis and analyzes the specific functional alterations observed in chronic and acute diseases of human central nervous system.
(3) Data acquisition of autophagy in the onset of neurodegenerative diseases benefits for clinical physicians to develop new treatment strategies in neurodegenerative diseases.
Accumulation of aberrant proteins and inclusion bodies are hallmarks in most neurodegenerative diseases. Consequently, these aggregates within neurons lead to toxic effects, overproduction of reactive oxygen species and oxidative stress. Autophagy is a significant intracellular mechanism that removes damaged organelles and misfolded proteins in order to maintain cell homeostasis. Excessive or insufficient autophagic activity in neurons leads to altered homeostasis and influences their survival rate, causing neurodegeneration. The review article provides an update of the role of autophagic process in representative chronic and acute neurodegenerative disorders.
(1) This study used a poly(3-hydroxybutyrate-co-3-hydroxyvalerate) nerve conduit, which has been shown to possess satisfactory biocompatibility and biodegradability, to repair a 30-mm-long sciatic nerve defect.
(2) At 4 months after surgery, the diameter of regenerated myelinated nerve fibers on the operated side of rats in the nanofibrous group was similar to that in the autograft group, the regenerated sciatic nerve fibers were continuous, myelinated and grew toward target skeletal muscle.
(3) Results from this study offer a novel solution for repair of long-segment peripheral nerve defects in the clinic.
It has been confirmed that nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate) nerve conduit can promote peripheral nerve regeneration in rats. However, its efficiency in repair of over 30-mm-long sciatic nerve defects needs to be assessed. In this study, we used a nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate) nerve conduit to bridge a 30-mm-long gap in the rat sciatic nerve. At 4 months after nerve conduit implantation, regenerated nerves were cally observed and histologically assessed. In the nanofibrous graft, the rat sciatic nerve trunk had been reconstructed by restoration of nerve continuity and formation of myelinated nerve fiber. There were Schwann cells and glial cells in the regenerated nerves. Masson's trichrome staining showed that there were no pathological changes in the size and structure of gastrocnemius muscle cells on the operated side of rats. These findings suggest that nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate) nerve conduit is suitable for repair of long-segment sciatic nerve defects.
(1) Astragaloside IV, the main component of the traditional Chinese medicine astragalus membranaceus, has been shown to exert neuroprotective effects, but studies regarding this compound are limited.
(2) This study assumed that astragaloside IV promoted the repair of sciatic nerve injury, and observed whether its mechanism of action was influenced by growth-associated protein-43 expression.
(3) Astragaloside IV accelerated nerve myelin sheath growth in mice with sciatic nerve injury, increased the diameter and number of myelinated nerve fibers, and elevated and accelerated pheral nerve regeneration and functional reconstruction by upregulating growth-associated tein-43 expression.
3-O-beta-D-xylopyranosyl-6-O-beta-D-glucopyranosyl-cycloastragenol (astragaloside IV), the main active component of the traditional Chinese medicine astragalus membranaceus, has been shown to be neuroprotective. This study investigated whether astragaloside IV could promote the repair of injured sciatic nerve. Denervated sciatic nerve of mice was subjected to anastomosis. The mice were intraperitoneally injected with 10, 5, 2.5 mg/kg astragaloside IV per day for 8 consecutive days. Western blot assay and real-time PCR results demonstrated that growth-associated protein-43 expression was upregulated in mouse spinal cord segments L4-6 after intervention with 10, 5, 2.5 mg/kg astragaloside IV per day in a dose-dependent manner. Luxol fast blue staining and electrophysiological detection suggested that astragaloside IV elevated the number and diameter of myelinated nerve fibers, and simultaneously increased motor nerve conduction velocity and action potential amplitude in the sciatic nerve of mice. These results indicated that astragaloside IV contributed to sciatic nerve regeneration and functional recovery in mice. The mechanism underlying this effect may be associated with the upregulation of growth-associated protein-43 expression.
(1) Previous treatment of spinal cord injury does not include protection of the motor endplate because the recovery of muscle motor function depends on the regeneration and reconstruction of the neuromuscular junction.
(2) No studies have reported the effect of basic fibroblast growth factor on anterior horn motor neurons and target organ neuromuscular junctions after spinal cord injury. Results showed that sic fibroblast growth factor can protect the endplate through increasing the expression of calcitonin gene related peptide and acetylcholinesterase in anterior horn motor neurons.
(3) This study also explored the characteristics of subarachnoid cavity administration, which may reduce side effects of systemic administration and directly transfer drugs to the injury site.
The distal end of the spinal cord and neuromuscular junction may develop secondary degeneration and damage following spinal cord injury because of the loss of neural connections. In this study, a rat model of spinal cord injury, established using a modified Allen's method, was injected with basic fibroblast growth factor solution via subarachnoid catheter. After injection, rats with spinal cord injury displayed higher scores on the Basso, Beattie and Bresnahan locomotor scale. Motor function was also well recovered and hematoxylin-eosin staining showed that spinal glial scar hyperplasia was not apparent. Additionally, anterior tibial muscle fibers slowly, but progressively, atrophied. nohistochemical staining showed that the absorbance values of calcitonin gene related peptide and acetylcholinesterase in anterior tibial muscle and spinal cord were similar, and injection of basic broblast growth factor increased this absorbance. Results showed that after spinal cord injury, the distal motor neurons and motor endplate degenerated. Changes in calcitonin gene related peptide and acetylcholinesterase in the spinal cord anterior horn motor neurons and motor endplate then occurred that were consistent with this regeneration. Our findings indicate that basic fibroblast growth factor can protect the endplate through attenuating the decreased expression of calcitonin gene related peptide and acetylcholinesterase in anterior horn motor neurons of the injured spinal cord.
(1) This review describes new insights into the structural biology of G-protein coupled receptors, with a focus on both allosteric and orthosteric binding, implying G-protein dependent and independent signaling pathways.
(2) The implications are explored for the design of new drugs to treat central nervous system disorders, such as Parkinson's and Alzheimer's disease.
In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selectivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and orthosteric binding sites on dopamine receptors for the treatment of Parkinson's disease, and on muscarinic receptors for Alzheimer's disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopamine receptor holds promise as a relevant therapeutic strategy for Parkinson's disease. Regarding the treatment of Alzheimer's disease, the design of dualsteric ligands for mono-oligomeric rinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.
(1) We investigated the temporal and spatial changes in the expression of protein disulfide isomerase A3, stress-induced-phosphoprotein 1 and heat shock cognate protein 70 in rabbit spinal cords after ischemia/reperfusion injury.
(2) Motor neurons became more vulnerable than interneurons after spinal cord ischemia/reperfusion injury. Increased expression of protein disulfide isomerase A3, stress-induced-phosphoprotein 1 and heat shock cognate protein 70 could protect neurons against injury.
(3) Hind limb functions were not positively associated with neuronal number within 48 hours after spinal cord ischemia/reperfusion injury. Edema was most obvious at 12 hours, which was induced by downregulation of various protein expressions.
(4) Elevating the expression of stress-related protein in neurons could be a new target for prevention and treatment of spinal cord ischemia/reperfusion injury.
Spinal cord ischemia/reperfusion injury is a stress injury to the spinal cord. Our previous studies using differential proteomics identified 21 differentially expressed proteins (n > 2) in rabbits with spinal cord ischemia/reperfusion injury. Of these proteins, stress-related proteins included protein disulfide isomerase A3, stress-induced-phosphoprotein 1 and heat shock cognate protein 70. In this study, we established New Zealand rabbit models of spinal cord ischemia/reperfusion injury by abdominal aorta occlusion. Results demonstrated that hind limb function initially improved after spinal cord ischemia/reperfusion injury, but then deteriorated. The pathological morphology of the spinal cord became aggravated, but lessened 24 hours after reperfusion. However, the numbers of motor neurons and interneurons in the spinal cord gradually decreased. The expression of protein disulfide isomerase A3, stress-induced-phosphoprotein 1 and heat shock cognate protein 70 was induced by ischemia/reperfusion injury. The expression of these proteins increased within 12 hours after reperfusion, and then decreased, reached a minimum at 24 hours, but subsequently increased again to similar levels seen at 6-12 hours, showing a characterization of induction-inhibition-induction. These three proteins were expressed only in cytoplasm but not in the nuclei. Moreover, the expression was higher in interneurons than in motor neurons, and the survival rate of interneurons was greater than that of motor neurons. It is assumed that the expression of stress-related proteins exhibited a protective effect on neurons.
(1) Degenerative alterations were found in noradrenergic neurons and fibers in the locus coeruleus of amyloid-&bgr; precursor protein and presenilin-1 double transgenic mice.
(2) The double transgenic mice had fewer noradrenergic neurons than wild types, because of death of noradrenergic neurons; the surviving noradrenergic neurons developed hypertrophy in the locus coeruleus.
(3) This study highlights the utility of amyloid-&bgr; precursor protein and presenilin-1 double transgenic mice in investigating catecholaminergic systems in Alzheimer's disease.
Mice carrying mutant amyloid-&bgr; precursor protein and presenilin-1 genes (APP/PS1 double transgenic mice) have frequently been used in studies of Alzheimer's disease; however, such studies have focused mainly on hippocampal and cortical changes. The severity of Alzheimer's disease is known to correlate with the amount of amyloid-&bgr; protein deposition and the number of dead neurons in the locus coeruleus. In the present study, we assigned APP/PS1 double transgenic mice to two groups according to age: young mice (5-6 months old) and aged mice (16-17 months old). Age-matched wild-type mice were used as controls. Immunohistochemistry for tyrosine hydroxylase (a marker of catecholaminergic neurons in the locus coeruleus) revealed that APP/PS1 mice had 23% fewer cells in the locus coeruleus compared with aged wild-type mice. APP/PS1 mice also had increased numbers of cell bodies of neurons positive for tyrosine hydroxylase, but fewer tyrosine hydroxylase-positive fibers, which were also short, thick and broken. Quantitative analysis using unbiased stereology showed a significant age-related increase in the mean volume of tyrosine droxylase-positive neurons in aged APP/PS1 mice compared with young APP/PS1 mice. Moreover, the mean volume of tyrosine hydroxylase-positive neurons was positively correlated with the total volume of the locus coeruleus. These findings indicate that noradrenergic neurons and fibers in the locus coeruleus are predisposed to degenerative alterations in APP/PS1 double transgenic mice.
(1) Cochlear gene therapy has been successfully used in the treatment of sensorineural hearing loss. Use of atonal homolog 1 gene delivered by viral vectors contributes to inner ear hair cell regeneration.
(2) Various types of viruses have been successfully used as vectors for transporting genes in the cochlea.
(3) Embryonic and adult inner ear neural stem cells can differentiate into hair cells.
Most recent studies on regeneration of inner ear hair cells focus on use of stem cells, gene therapy and neurotrophic factors. Cochlear gene therapy has been successfully used in the treatment of neurosensory hearing loss. This suggests that cochlear hair cell regeneration is possible. The objective of this paper is to review research and clinical application of inner near hair cell regeneration.
(1) This study first verified that combined glial-restricted precursor-derived astrocytes induced by bone morphogenetic protein-4 and human recombinant decorin transplantation inhibited early inflammatory reactions and protected axons in rats with T8 spinal cord contusion, inhibited astrocyte proliferation and glial scar formation, and promoted axonal regeneration and growth, all of which contributed to the recovery of motor and sensory functions below the level of spinal cord contusion.
(2) This combined transplantation provides a potential new therapy for experimental research and clinical transformation for the repair of spinal cord injury.
Following spinal cord injury, astrocyte proliferation and scar formation are the main factors inhibiting the regeneration and growth of spinal cord axons. Recombinant decorin suppresses inflammatory reactions, inhibits glial scar formation, and promotes axonal growth. Rat models of T8 spinal cord contusion were created with the NYU impactor and these models were subjected to combined transplantation of bone morphogenetic protein-4-induced glial-restricted precursor-derived astrocytes and human recombinant decorin transplantation. At 28 days after spinal cord contusion, double-immunofluorescent histochemistry revealed that combined transplantation inhibited the early inflammatory response in injured rats. Furthermore, brain-derived neurotrophic factor, which was secreted by transplanted cells, protected injured axons. The combined transplantation promoted axonal regeneration and growth of injured motor and sensory neurons by inhibiting astrocyte proliferation and glial scar formation, with astrocytes forming a linear arrangement in the contused spinal cord, thus providing axonal regeneration channels.