(1) Growing evidence has highlighted that oxidative stress and mitochondrial dysfunction may trigger neurodegenerative diseases.
(2) The contribution of oxidative stress-caused mitochondrial damage in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis is summarized and analyzed, in a broad attempt to provide evidence for the potential treatment of neurodegenerative diseases.
Oxidative stress and mitochondrial damage have been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Oxidative stress is characterized by the overproduction of reactive oxygen species, which can induce mitochondrial DNA mutations, damage the mitochondrial respiratory chain, alter membrane permeability, and influence Ca2+ homeostasis and mitochondrial defense systems. All these changes are implicated in the development of these neurodegenerative diseases, mediating or amplifying neuronal dysfunction and triggering neurodegeneration. This paper summarizes the contribution of oxidative stress and mitochondrial damage to the onset of neurodegenerative eases and discusses strategies to modify mitochondrial dysfunction that may be attractive therapeutic interventions for the treatment of various neurodegenerative diseases.
(1) Calpain participates in gentamicin-, neomycin- and kanamycin-induced inner ear cell apoptosis. Cisplatin has been shown to be an anticancer drug. However, cisplatin can lead to severe ototoxicity, induce cochlear cell apoptosis, and result in hearing decrease or loss, which limits the application of cisplatin in a clinical setting to a certain degree.
(2) Cisplatin has been shown to activate transient receptor potential V1 and cause Ca2+ influx and overload, finally resulting in cochlear hair cell injury and death. Thus, it remains unclear whether calpain expression was detected during cisplatin-induced cochlear hair cell death.
(3) This study established a BALB/c mouse model of cisplatin-induced ototoxicity. Calpain sion in the mouse cochlea was observed and the possible effect of calpain on cisplatin-induced ototoxicity was explored using immunofluorescence staining, image analysis and western blotting, in combination with an auditory brainstem response test.
(4) Results from this study verified that cisplatin upregulated calpain 1 and calpain 2 expression in the mouse cochlea in a dose-dependent manner, and that calpain 2 plays a leading role in this process.
Ototoxic drug-induced apoptosis of inner ear cells has been shown to be associated with calpain expression. Cisplatin has severe ototoxicity, and can induce cochlear cell apoptosis. This study assumed that cisplatin activated calpain expression in apoptotic cochlear cells. A mouse model of cisplatin-induced ototoxicity was established by intraperitoneal injection with cisplatin (2.5, 3.5, 4.5, 5.5 mg/kg). Immunofluorescence staining, image analysis and western blotting were used to detect the expression of calpain 1 and calpain 2 in the mouse cochlea. At the same time, the auditory brainstem response was measured to observe the change in hearing. Results revealed that after intraperitoneal injection with cisplatin for 5 days, the auditory brainstem response threshold shifts increased in mice. Calpain 1 and calpain 2 expression significantly increased in outer hair cells, the spiral ganglion and stria vascularis. Calpain 2 protein expression markedly increased with an increased dose of cisplatin. Results suggested that calpain 1 and calpain 2 mediated cisplatin-induced ototoxicity in BALB/c mice. During this process, calpain 2 plays a leading role.
(1) This study concluded that decimeter wave therapy promoted the proliferation of Schwann cells and elevated S-100 protein expression in injured sciatic nerves, and contributed to neural regeneration and functional recovery at cellular and molecular levels.
(2) Decimeter wave therapy promoted axonal regeneration and remyelination, delayed myatrophy and facilitated neural regeneration and functional recovery.
(3) Decimeter wave therapy inhibited the inflammatory reaction and anticoagulation, improved the local blood circulation, reduced the formation of scar and effectively prevented nerve adhesion and re-entrapment after repairing.
Drug treatment, electric stimulation and decimeter wave therapy have been shown to promote the repair and regeneration of the peripheral nerves at the injured site. This study prepared a Mackinnon's model of rat sciatic nerve compression. Electric stimulation was given immediately after neurolysis, and decimeter wave radiation was performed at 1 and 12 weeks post-operation. Histological observation revealed that intraoperative electric stimulation and decimeter wave therapy could improve the local blood circulation of repaired sites, alleviate hypoxia of compressed nerves, and lessen adhesion of compressed nerves, thereby decreasing the formation of new entrapments and enhancing compressed nerve regeneration through an improved microenvironment for regeneration. Immunohistochemical staining results revealed that intraoperative electric stimulation and decimeter wave could promote the expression of S-100 protein. Motor nerve conduction velocity and amplitude, the number and diameter of myelinated nerve fibers, and sciatic functional index were significantly increased in the treated rats. These results verified that intraoperative electric stimulation and decimeter wave therapy contributed to the regeneration and the recovery of the functions in the compressed nerves.
(1) After poly(lactic-co-glycolic acid) conduit transplantation and autogenous nerve grafting of in vitro models of sciatic nerve injury using human cadaver sciatic nerves, longitudinal tensile tests were conducted, and stress and strain data of sciatic nerves were obtained. This provided biomechanical basis for poly(lactic-co-glycolic acid) conduit transplantation in the repair of injured sciatic nerve.
(2) Poly(lactic-co-glycolic acid) conduits (ratio of lactic acid to glycolic acid = 70:30) were fabricated using NaCl as a pore-foaming agent. The mass ratio of poly(lactic-co-glycolic acid) to NaCl was 1:9. After transplantation, the poly(lactic-co-glycolic acid) conduit exhibited a definite intensity, elasticity and plasticity and can be used for sciatic nerve injury transplantation.
Tensile stress and tensile strain directly affect the quality of nerve regeneration after bridging nerve defects by poly(lactic-co-glycolic acid) conduit transplantation and autogenous nerve grafting for sciatic nerve injury. This study collected the sciatic nerve from the gluteus maximus muscle from fresh human cadaver, and established 10-mm-long sciatic nerve injury models by removing the ischium, following which poly(lactic-co-glycolic acid) conduits or autogenous nerve grafts were transplanted. Scanning electron microscopy revealed that the axon and myelin sheath were torn, and the vessels of basilar membrane were obstructed in the poly(lactic-co-glycolic acid) conduit-repaired sciatic nerve following tensile testing. There were no significant differences in tensile tests with autogenous nerve graft-repaired sciatic nerve. Following poly(lactic-co-glycolic acid) conduit transplantation for sciatic nerve repair, tensile test results suggest that maximum tensile load, maximum stress, elastic limit load and elastic limit stress increased compared with autogenous nerve grafts, but elastic limit strain and maximum strain decreased. Moreover, the tendencies of stress-strain curves of sciatic nerves were similar after transplantation of poly(lactic-co-glycolic acid) conduits or autogenous nerve grafts. Results showed that after transplantation in vitro for sciatic nerve injury, poly(lactic-co-glycolic acid) conduits exhibited good intensity, elasticity and plasticity, indicating that poly(lactic-co-glycolic acid) conduits are suitable for sciatic nerve injury repair.
(1) The acellular nerve allografts prepared in this study were completely decellularized, with an intact structure remaining. The laminin and basilar membrane, which could promote axonal growth, were also retained.
(2) Scanning electron microscope showed that the prepared acellular nerve allografts had a good affinity to the in vitro cultured bone marrow mesenchymal stem cells, which were evenly distributed in the grafts.
(3) Under the induction of acellular nerve allografts and the in vivo regeneration microenvironment, bone marrow mesenchymal stem cells with multiple differentiation potential could differentiate into Schwann cells, and promote the axons at the proximal end of 15 mm sciatic nerve defects to grow towards the distal end, thus improving the motor functional recovery of rat hind limbs.
In this study, we constructed tissue-engineered nerves with acellular nerve allografts in Sprague-Dawley rats, which were prepared using chemical detergents-enzymatic digestion and mechanical methods, in combination with bone marrow mesenchymal stem cells of Wistar rats cultured in vitro, to repair 15 mm sciatic bone defects in Wistar rats. At postoperative 12 weeks, electrophysiological detection results showed that the conduction velocity of regenerated nerve after repair with tissue-engineered nerves was similar to that after autologous nerve grafting, and was higher than that after repair with acellular nerve allografts. Immunohistochemical staining revealed that motor endplates with acetylcholinesterase-positive nerve fibers were orderly arranged in the middle and superior parts of the gastrocnemius muscle; regenerated nerve tracts and sprouted branches were connected with motor endplates, as shown by acetylcholinesterase histochemistry combined with silver staining. The wet weight ratio of the tibialis anterior muscle at the affected contralateral hind limb was similar to the sciatic nerve after repair with autologous nerve grafts, and higher than that after repair with acellular nerve allografts. The hind limb motor function at the affected side was significantly improved, indicating that acellular nerve allografts combined with bone marrow mesenchymal stem cell bridging could promote functional recovery of rats with sciatic nerve defects.
(1) Atorvastatin increases inducible nitric oxide synthase protein levels in the parietal cortex whereas decreases inducible nitric oxide synthase protein levels in the liver of aged beagles
(2) Up-regulation of inducible nitric oxide synthase and heme oxygenase-1 are positively associated with biliverdin reductase-A protein levels and activity.
(3) Down-regulation of inducible nitric oxide synthase and heme oxygenase-1 are negatively associated with biliverdin reductase-A oxidation
Alzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer's disease, but the exact mechanisms of action are still unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer's disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated that atorvastatin treatment (80 mg/day for 14.5 months) to aged beagles selectively increased inducible nitric oxide synthase in the parietal cortex but not in the cerebellum. In contrast, inducible nitric oxide synthase protein levels were significantly decreased in the liver. Significant positive correlations were found between biliverdin reductase-A and inducible nitric oxide synthase as well as heme oxygenase-1 protein levels in the parietal cortex. The opposite was observed in the liver. Inducible nitric oxide synthase up-regulation in the parietal cortex was positively associated with improved biliverdin reductase-A functions, whereas the oxidative-induced impairment of biliverdin reductase-A in the liver negatively affected inducible nitric oxide synthase expression, thus suggesting a role for biliverdin reductase-A in atorvastatin-dependent inducible nitric oxide synthase changes. Interestingly, increased inducible nitric oxide synthase levels in the parietal cortex were not associated with higher oxidative/nitrosative stress levels. We hypothesize that biliverdin reductase-A-dependent inducible nitric oxide synthase regulation strongly contributes to the cognitive improvement observed following atorvastatin treatment.
(1) X-linked methyl-CpG binding protein 2 and tyrosine hydroxylase expression is reduced in 6-hydroxydopamine-treated cells.
(2) Overexpression of X-linked methyl-CpG binding protein 2 in SH-SY5Y cells reduced cell apoptosis induced by 6-hydroxydopamine and increased tyrosine hydroxylase expression.
(3) X-linked methyl-CpG binding protein 2 inhibited 6-hydroxydopamine-induced apoptosis by increasing tyrosine hydroxylase expression in SH-SY5Y cells.
(4) X-linked methyl-CpG binding protein 2 may be a potential therapeutic target for Parkinson's disease.
X-linked methyl-CpG binding protein 2 mutations can induce symptoms similar to those of Parkinson's disease and dopamine metabolism disorders, but the specific role of X-linked methyl-CpG binding protein 2 in the pathogenesis of Parkinson's disease remains unknown. In the present study, we used 6-hydroxydopamine-induced human neuroblastoma cell (SH-SY5Y cells) injury as a cell model of Parkinson's disease. The 6-hydroxydopamine (50 μmol/L) treatment decreased protein levels for both X-linked methyl-CpG binding protein 2 and tyrosine hydroxylase in these cells, and led to cell death. However, overexpression of X-linked methyl-CpG binding protein 2 was able to ameliorate the effects of 6-hydroxydopamine, it reduced 6-hydroxydopamine-induced apoptosis, and increased the levels of tyrosine hydroxylase in SH-SY5Y cells. These findings suggesting that X-linked methyl-CpG binding protein 2 may be a potential therapeutic target for the treatment of Parkinson's disease.
(1) We investigated the mechanism of action of striatal-enriched phosphatase 61 at the behavioral and signaling molecule levels, using in vivo and in vitro models. We discussed the relationship of striatal-enriched phosphatase 61 with transgene and N-methyl-D-aspartate receptor 2B, and lyzed the molecular mechanism by which striatal-enriched phosphatase 61 regulates N-methyl-D-aspartate receptor 2B transport.
(2) Spatial learning and memory deficits in Alzheimer's disease may be associated with disturbed N-methyl-D-aspartate receptor 2B transport caused by striatal-enriched phosphatase 61. RNA silencing can effectively inhibit striatal-enriched phosphatase 61 target gene expression and can be used to investigate the function and involvement of striatal-enriched phosphatase 61 in the pathogenesis of Alzheimer's disease.
(3) This study provides a basic reference for gene therapy for Alzheimer's disease using striatal-enriched phosphatase 61.
To stop the progression of Alzheimer's disease in the early stage, it is necessary to identify new therapeutic targets. We examined striatal-enriched phosphatase 61 expression in the brain tissues of 12-month-old APPswe/PSEN1dE9 transgenic mice. Immunohistochemistry showed that al-enriched phosphatase 61 protein expression was significantly increased but phosphorylated N-methyl-D-aspartate receptor 2B levels were significantly decreased in the cortex and hippocampus of APPswe/PSEN1dE9 transgenic mice. Western blotting of a cell model of Alzheimer's disease consisting of amyloid-beta peptide (1-42)-treated C57BL/6 mouse cortical neurons in vitro showed that valeric acid (AP5), an N-methyl-D-aspartate receptor antagonist, significantly inhibited amyloid-beta 1-42-induced increased activity of striatal-enriched phosphatase 61. In addition, the phosphorylation of N-methyl-D-aspartate receptor 2B at Tyr1472 was impaired in amyloid-beta 1-42-treated cortical neurons, but knockdown of striatal-enriched phosphatase 61 enhanced the phosphorylation of N-methyl-D-aspartate receptor 2B. Collectively, these findings indicate that striatal-enriched phosphatase 61 can disturb N-methyl-D-aspartate receptor transport and inhibit the progression of learning and study disturbances induced by Alzheimer's disease. Thus, al-enriched phosphatase 61 may represent a new target for inhibiting the progression of Alzheimer's disease.
In multiple sclerosis, gray matter atrophy is extensive, and cognitive deficits and mood disorders are frequently encountered. It has been conjectured that focal atrophy is associated with emotional decline. However, conventional MRI has revealed that the pathological characteristics cannot fully account for the mood disorders. Moreover, there is no correlation between cognitive disorders and MRI results in clinically isolated syndromes or in cases of definite multiple sclerosis. In this case-control study, voxel-based morphometric analysis was performed on 11 subjects with relapsing-remitting multiple sclerosis, and the results show that these patients exhibit gray matter atrophy. Moreover, the gray matter atrophy in the superior and middle gyri of the right frontal lobe in patients with multiple sclerosis was correlated with scores from the Hamilton Anxiety Rating Scale. The scores obtained with the Repeatable Battery for the Assessment of Neuropsychological Status were associated with gray matter atrophy in the middle gyrus of the left frontal lobe, the superior and middle gyrus of the right frontal lobe, the middle gyrus of the left cingulate, the superior and middle gyri of the left frontal lobe, and the triangular area of the left frontal lobe. However, there was no statistical significance. These findings suggest that the cingulate and frontal cortices of the nant hemisphere are the most severely atrophic regions of the brain, and this atrophy is correlated with cognitive decline and emotional abnormalities.