Alpha-lipoic acid ALA exhibits a strong neuroprotective effect. It is used to treat diseases caused by oxidative stress OS such as diabetic neuropathy [ 10 ] and multiple sclerosis [ 11 ] and to alleviate the inflammatory response [ 12 ]. It is also used as a modulator of various inflammatory signaling pathways [ 13 ].

As early in , Melli et al. reported that ALA is neuroprotective in sensory neurons and prevents apoptosis of DRG cells [ 14 ].

A later study found that ALA reduces expression of oxides and increases antioxidants in sciatic nerve crush injury rat models [ 15 ]. We thus wondered whether ALA would have neuroprotective effects in PNI.

In the present study, we employed chronic constriction injury CCI in rats as a model of chronic neuropathic pain [ 16 ] and P53 as a cellular apoptosis marker.

The aim was to look for evidence of neuroprotective effects of ALA in CCI rat models, potentially leading to a novel treatment for neuropathic pain associated with PNI. Food and water were provided ad libitum.

The animals were randomly divided into three groups. Ethical approval: The research related to animal use has been complied with all the relevant national regulations and institutional policies for the care and use of animals and was approved and supervised by the Animal Care and Use Committee of the First Affiliated Hospital of Zhengzhou University.

The CCI models were established according to the methods described in a previous study [ 16 ]. The right sciatic nerve was exposed at the level of the mid-thigh, and the connective tissue around the nerve was cleared.

To assess the pain, mechanical and thermal nociceptive thresholds were examined as previously described [ 19 ]. To examine the mechanical nociceptive threshold, animals were placed individually into a small plastic cage with an open wire mesh bottom. Von Frey filaments North Coast Medical Inc, Morgan Hill, CA, ranged from 1.

One of the tactile-defensive behaviorals, namely, brisk paw withdrawal was observed. Filaments were used in ascending order. Each filament was used once prior to advancing to the next filament. The smallest filament that conducted a paw withdrawal response was considered the threshold stimulus.

The paw withdrawal threshold PWT index was recorded and averaged over five measurements. For thermal nociceptive thresholds, animals were placed in an acrylic box with a transparent glass plate and irradiated with radiant heat on both hind paws. The leg lift avoidance time the time it took to respond to the thermal stimulus was counted as the paw withdrawal latency PWL.

The behavioral assessments were performed 1 day before surgery and 3, 7, 14, and 21 days postsurgery. Animals were kept in the testing chambers for 30 minutes before each measurement so as to ensure they were accustomed to the test environment. After the behavioral tests, all animals were submitted to the morphological experiments.

DRG tissues were examined morphologically for evidence of nerve damage with hematoxylin and eosin HE staining and for cellular apoptosis with P53 immunohistochemical staining. After rinsing, the DRG tissues were processed and embedded in paraffin. Some tissue sections were examined after standard HE staining.

The remaining sections were submitted to P53 staining. To determine P53 immunoreactivity, anti-P53 mouse monoclonal antibodies , ZM, ZSGB-BIO, Beijing, China were applied to the sections overnight at 4°C. Diaminobenzidine color reagent SN, Celnovte Biotechnology, Henan, China was used to develop color.

The SGCs surrouding the neurons were identified using the methods described by a previous study [ 20 ]. Briefly, all the sections were observed and quantitatively analyzed using a slice-analyzing system including an optical microscope Nikon Ni-E, Japan and the Image J 1.

The processes of the images included converting the image to black and white, subtracting the background, elevating contrast, reducting the noise, and finally perfoming measurements. In this study, we set all DRG areas ipsilateral to injury as the regions of interest ROI.

A standard Erode and Dilate filter was employed to reduce the background noise. Dilate was used in the cell area to obtain a value comparable to the area before applying the Erode filter.

Image binarization was performed to correct filter operations. Using these methods, the edematous DRG neurons and surrounding SGCs were identified. All these processes were performed by the same experienced researcher blinded to the treatments of groups.

Data were analyzed using SPSS software V All data are reported as mean ± standard deviation. All statistical results were tested on both sides. Normality of distribution and homogeneity of variance tests were performed first.

Analysis of variance followed by Bonferroni post hoc correction was then selected for multiple comparisons. CCI treatment significantly shortened the PWT Figure 1a and PWL Figure 1b as compared with the sham group. These changes were partly ameliorated by ALA treatment, although not to the normal levels of the sham group.

The same differences between groups were present at postoperative days 3, 7, 14, and 21 Figure 1. Changes in paw withdrawal thresholds PWTs and paw withdrawal latency PWL induced by chronic constriction injury CCI and its treatment with alpha-lipoic acid ALA.

a The PWTs in the CCI group were significantly lower than those in the sham group, whereas ALA treatment significantly enhanced PWTs, although not to the level of the sham group. b Similar to the PWTs, the PWLs of the CCI group were significantly lower than those of the sham group.

Treatments with ALA significantly enhanced the PWLs, although not to the level of the sham group. In the sham group, DRG cells appeared morphologically normal Figure 2a. No edema or abnormal aggregation or proliferation of cells was observed.

In the CCI group, the cell bodies of DRG neurons were markedly edematous with evident vacuolar-like changes Figure 2b. The cytoplasm was concentrated, and the cell body volume contracted and deformed. Occasionally, apoptotic neuronal cells were observed, and the number of SGCs was obviously enhanced.

Such changes indicated an enhanced inflammatory reaction associated with CCI. Morphology of dorsal root ganglia DRG and satellite glial cells SGC hematoxylin and eosin.

a Representative photo of DRG cells in the sham group with normally shaped neuronal cells. b Representative photo of DRG cells in the CCI group. Edematous neurons and the enhanced SCGs surrounding the neurons can be observed. Although there are some edematous neurons and enhanced SGCs, they are fewer than in the CCI group.

ALA treatment partially relieved this effect, although without restoring the DRG tissues to normal at both 7 and 21 days after operation. This suggests that ALA treatment partly relieves the inflammatory reaction induced by CCI Figure 2d—f.

The findings were similar at both 7 days Figure 3c and 21 days Figure 3d postoperatively. P53 immunohistochemistry of dorsal root ganglia DRG after chronic compression injury CCI. Representative photo of P53 staining of DRGs in the sham group, a 7 and b 21 days after operation.

Representative photos of P53 staining in CCI group, c 7 and d 21 days after operation. The brown areas indicate apoptosis cells, which are small and shrunken. The present study used ALA to treat chronic neuropathic pain in a CCI rat model.

Our findings have therefore provided behavioral Figure 1 , morphologic Figure 2 , and immunohistochemical Figure 3 evidence that we successfully established a CCI-induced PNI model in rats. We also demonstrated that ALA treatment partially relieved the CCI-induced pathologic changes.

We have therefore verified the protective effects of ALA on chronic neuropathic pain. These findings imply that ALA can be considered as a potential therapy for PNI-associated neuropathic pain, although further verification is needed. The CCI rat model used in the present study is a classic model used to mimic chronic neuropathic pain [ 22 ].

Sciatic nerve ligation damages the peripheral nerve, so that the animal may try to bite the injured leg off. This abnormal behavior is regarded as a reaction to neuropathic pain [ 22 , 23 ].

In measurements of mechanical and thermal nociceptive thresholds, the PWT as well as PWL may shorten because of changes such as hyperpathia caused by CCI. Our behavioral data pointed a significant decreases in PWT and PWL after CCI, in accordance with a previous study [ 24 ].

Along with the morphologic and immunohistochemical evidence, our findings confirmed that we successfully established this CCI rat model. ALA treatment prolonged the PWT and PWL in the treatment group, indicating that it reduced hyperpathia, thus confirming the efficacy of ALA treatment.

Differing from astrocytes or oligodendrocytes, SGCs are a distinct type of glial cells that surround sensory neurons in ganglia of the peripheral nervous system. The role of SGCs is not fully understood, although studies have indicated they play a crucial role in neuropathic pain, including visceral [ 25 ] and peripheral neuropathic pain [ 26 , 27 ].

A number of studies have demonstrated that a variety of injurious stimuli may trigger activation of SGCs [ 27 , 28 , 29 ]. SGC activation is regarded as a neurophysiologic reaction to neuronal stress induced by these stimuli [ 26 ].

Activated SGCs commonly have remarkable cellular proliferation [ 28 ]. HE staining in our CCI rat models showed proliferated and abnormally aggregated SGCs. Along with other abnormal morphologic manifestations in the DRG neurons, we confirmed that the CCI procedure induces neurologic damage.

ALA treatment reduced these physiologic changes, by reducing the enhancement of SGCs, ameliorating edema in the neurons, and normalizing the shape of the neurons.

Therefore through relieving the neuronal stress state, ALA proved to have a neuroprotective effect. Our findings using P53 immunohistochemistry also strengthened the evidence of that. P53 protein is a crucial player in the cellular response to neuronal stress [ 30 ].

P53 staining is employed as a biomarker of Pinduced apoptosis [ 31 , 32 ]. The P53 gene has been shown to play a vital modulatory role in neuropathic pain induced by DRG trauma [ 33 ]. Similarly, we found that P53 expression was significantly upregulated in the CCI rat model, paralleling the morphologic changes.

This indicates that CCI promotes cellular apoptosis. This is further evidence that ALA can ameliorate CCI-induced damage mediated by Pinduced apoptosis. Although our study provided several different types of evidence of the efficacy of ALA in this model of neuropathic pain, the mechanisms by which it functions need further investigation.

Reducing Pinduced apoptosis is one potential mechanism. It has been shown that neuronal apoptosis serves as a mechanism to maintain neuropathic pain, while suppression of cellular apoptosis ameliorates hyperalgesia and mechanical abnormal pain [ 34 ], which completely agrees with our findings in the present study.

The mechanisms underlying cellular apoptosis may be closely associated with OS [ 34 , 35 , 36 ]. Battisti et al. used ALA to treat chronic low back pain, finding that ALA and superoxide dismutase SOD exhibited a synergistic effect to reduce neuropathic pain.

This suggests that ALA might have a neuroprotective effect at least in part by reducing the OS that would otherwise cause neuropathic pain [ 36 ]. Using ALA to treat mechanical PNI has been shown to activate SOD and catalase [ 37 ]. All the evidence strongly suggests that OS-related mechanisms may be critically important in the neuroprotective effects of ALA on the neuropathic pain associated with PNI.

Future study is required to further investigate these mechanisms. There are several limitations in this study. First, we did not perform immunohistochemical staining for SGCs.

Although using the methods introduced by Manzhulo et al. Although no animal died in this study, previous study in diabetic rats reported that diabetic rats died in this dose [ 18 ]. Unfortunately, we did not perform a preliminary experiment to determine the most optimal dose of ALA for CCI.

All these limitations should be addressed in our future investigation. Taken together, our study indicates neuroprotective effects of ALA on chronic neuropathic pain in a CCI rat model.

Our results imply that ALA can be considered as a potential therapy for the neuropathic pain associated with PNI. Further verification with clinical testing, as well as exploring the therapeutic mechanisms, is required.

Funding: This study was supported by grants from the Japanese Society for the Promotion of Science Grant-in-Aid for Young Scientists, Type B, No. Conflict of interest: The authors state no conflict of interest.

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The aim of this study is to investigate the neuroprotective and anti-apoptotic effects of alpha-lipoic acid on spinal cord ischemia—reperfusion. The abdominal aorta was clamped for 30 min by an aneurysm clip, approximately 1 cm below the renal artery and 1 cm above the iliac bifurcation in control and treatment groups.

Only laparotomy was performed in the sham group. The animals were killed 48 h later. Spinal cord segments between L2 and S1 were harvested for analysis.

Levels of nitric oxide, glutathione, malondialdehyde, advanced oxidation protein products, and superoxide dismutase were analyzed as markers of oxidative stress and inflammation. Caspase-3 activity was analyzed to detect the effect of lipoic acid on apoptosis.

In all measured parameters of oxidative stress, administration of lipoic acid significantly demonstrated favorable effects. Both plasma and tissue levels of nitric oxide, glutathione, malondialdehyde, and advanced oxidation protein products significantly changed in favor of antioxidant activity.

There was no significant difference between the plasma superoxide dismutase levels of the groups. Histopathological evaluation of the tissues also demonstrated significant decrease in cellular degeneration and infiltration parameters after lipoic acid administration. However, lipoic acid has no effect on caspase-3 activity.

Although further studies considering different dose regimens and time intervals are required, the results of the present study prove that alpha-lipoic acid has favorable effects on experimental spinal cord ischemia—reperfusion injury.

This is a preview of subscription content, log in via an institution to check access. Rent this article via DeepDyve. Institutional subscriptions.

Amar AP, Levy ML Pathogenesis and pharmacological strategies for mitigating secondary damage in acute spinal cord injury. Neurosurgery —, discussion — Article PubMed CAS Google Scholar. Aykac G, Uysal M, Yalcin AS, Kocak-Toker N, Sivas A, Oz H The effect of chronic ethanol ingestion on hepatic lipid peroxide, glutathione, glutathione peroxidase and glutathione transferase in rats.

Toxicology — Azbill RD, Mu X, Bruce-Keller AJ, Mattson MP, Springer JE Impaired mitochondrial function, oxidative stress and altered antioxidant enzyme activities following traumatic spinal cord injury.

Brain Res — Baptiste DC, Fehlings MG Pharmacological approaches to repair the injured spinal cord. J Neurotrauma — Article PubMed Google Scholar. Bilska A, Wlodek L Lipoic acid—the drug of the future? Pharmacol Rep — PubMed CAS Google Scholar.

Bowes MP, Swanson S, Zivin JA The AMPA antagonist LY improves functional neurological outcome following reversible spinal cord ischemia in rabbits. J Cereb Blood Flow Metab — Bracken MB, Shepard MJ, Holford TR, Leo-Summers L, Aldrich EF, Fazl M, Fehlings MG, Herr DL, Hitchon PW, Marshall LF, Nockels RP, Pascale V, Perot PL Jr, Piepmeier J, Sonntag VK, Wagner F, Wilberger JE, Winn HR, Young W Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury: 1-year follow up.

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Free Radic Res — Casini AF, Ferrali M, Pompella A, Maellaro E, Comporti M Lipid peroxidation and cellular damage in extrahepatic tissues of bromobenzene-intoxicated mice. Am J Pathol — Chaudhary P, Marracci GH, Bourdette DN Lipoic acid inhibits expression of ICAM-1 and VCAM-1 by CNS endothelial cells and T cell migration into the spinal cord in experimental autoimmune encephalomyelitis.

J Neuroimmunol — Christie SD, Comeau B, Myers T, Sadi D, Purdy M, Mendez I Duration of lipid peroxidation after acute spinal cord injury in rats and the effect of methylprednisolone. Neurosurg Focus E5. J Cardiothorac Surg Conti A, Miscusi M, Cardali S, Germano A, Suzuki H, Cuzzocrea S, Tomasello F Nitric oxide in the injured spinal cord: synthases cross-talk, oxidative stress and inflammation.

Brain Res Rev — Diaz-Ruiz A, Rios C, Duarte I, Correa D, Guizar-Sahagun G, Grijalva I, Madrazo I, Ibarra A Lipid peroxidation inhibition in spinal cord injury: cyclosporin-A vs methylprednisolone.

NeuroReport — Dumont RJ, Okonkwo DO, Verma S, Hurlbert RJ, Boulos PT, Ellegala DB, Dumont AS Acute spinal cord injury, part I: pathophysiologic mechanisms. Clin Neuropharmacol — Dumont RJ, Verma S, Okonkwo DO, Hurlbert RJ, Boulos PT, Ellegala DB, Dumont AS Acute spinal cord injury, part II: contemporary pharmacotherapy.

Erten SF, Kocak A, Ozdemir I, Aydemir S, Colak A, Reeder BS Protective effect of melatonin on experimental spinal cord ischemia. Spinal Cord — Genovese T, Cuzzocrea S Role of free radicals and poly ADP-ribose polymerase-1 in the development of spinal cord injury: new potential therapeutic targets.

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Am J Obstet Gynecol — Download references. Department of Neurosurgery, Faculty of Medicine, Gazi University, Polikliniği Kat 1, Ankara, , Turkey. Kemali Baykaner. Department of Biochemistry, Faculty of Medicine, Gazi University, Ankara, , Turkey. Department of Histology and Embryology, Faculty of Medicine, Gazi University, Ankara, , Turkey.

You can also search for this author in PubMed Google Scholar. Correspondence to Hakan Emmez. Currently, there is a tremendous research focus in animals and humans to improve the devastating effects of spinal cord injury.

Some of the main strategies include avoidance of prehospital hypoxia and hypotension, early surgical decompression and spinal fracture stabilization, therapeutic hypothermia, neuroprotectants such as alpha-lipoic acid in this study, neurotrophic agents, cell transplantation, blocking myelin-based protein inhibitors, using neural scaffolds, anti-inflammatory agents, reducing glial scar formation, and new rehabilitation strategies.

Emmez and colleagues have reported a carefully conducted study using the antioxidant alpha-lipoic acid in an experimental spinal cord ischemia and reperfusion injury model in 24 rabbits.

The animals were sacrificed 48 h after the injury was induced, and it was found that tissue and spinal cord tissue levels of various markers of oxidative stress were significantly improved and there was less cellular degeneration and inflammatory change in the affected spinal cord after intraperitoneal alpha-lipoic acid was administered shortly after 30 min of ischemia.

This experiment is a long way from the use of this agent in human spinal cord injury but is an important step along the way. There is a component of ischemia—reperfusion injury in human spinal cord injury, but there is also the mechanical injury.

The ischemia—reperfusion injury model the authors have used is not therefore a complete model of human spinal cord injury. This antioxidant should be further investigated experimentally with different dose scales, administered at different time intervals after the trauma, for longer observation periods, and with different models such as weight drop or clamping that more closely replicate mechanical injury to the spinal cord or parts of it before sacrifice of the animals.

Clearly there are ethical challenges to keeping animals alive longer after partial or complete spinal cord injury. We encourage the authors to continue their excellent research on this promising therapeutic agent.

Departments of Neurosurgery and Surgery, The Alfred Hospital and Monash University, Melbourne, Australia. Reprints and permissions. Emmez, H. et al. Anti-apoptotic and neuroprotective effects of alpha-lipoic acid on spinal cord ischemia—reperfusion injury in rabbits.

Acta Neurochir , — Download citation. Received : 11 January Accepted : 24 May Published : 10 June Issue Date : September Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative. Abstract Purpose Radical oxygen species produced after injury counteracts antioxidant activity and frequently causes severe oxidative stress for the tissues.

Results In all measured parameters of oxidative stress, administration of lipoic acid significantly demonstrated favorable effects. Conclusions Although further studies considering different dose regimens and time intervals are required, the results of the present study prove that alpha-lipoic acid has favorable effects on experimental spinal cord ischemia—reperfusion injury.

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