The Neurotoxicity of Epidural Hyaluronic Acid in Rabbits: A Light and Electron Microscopic Examination

Lim, Young-Jin; Sim, Woo-Seok; Kim, Yong-Chul; Lee, Sangchul; Choi, Yoon–La

doi:10.1213/01.ane.0000087044.16739.5a

Cited by 14 publications

(7 citation statements)

References 10 publications

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“…EM findings showed no significant neurotoxic findings in either group. In conclusion, epidurally-administered HA did not cause neurotoxicity in rabbits (Lim et al, 2003).…”

Section: Neurotoxicitymentioning

confidence: 67%

Hyaluronic acid (hyaluronan): a review

Nečas¹,

Bartošíková²,

Brauner³

et al. 2008

Vet. Med.

820

646

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Hyaluronic acid (HA) is a high molecular weight biopolysacharide, discovered in 1934, by Karl Meyer and his assistant, John Palmer in the vitreous of bovine eyes. Hyaluronic acid is a naturally occurring biopolymer, which has important biological functions in bacteria and higher animals including humans. It is found in most connective tissues and is particularly concentrated in synovial fluid, the vitreous fluid of the eye, umbilical cords and chicken combs. It is naturally synthesized by a class of integral membrane proteins called hyaluronan synthases, and degraded by a family of enzymes called hyaluronidases. This review describes metabolisms, different physiological and pathological functions, basic pharmacological properties, and the clinical use of hyaluronic acid. Keywords: hyaluronic acid; metabolism; toxicityList of abbreviations CD44 = cell surface glycoprotein; CDC37 = intracellular HA-binding protein; Da = dalton; DNA = deoxynucleotid acid; ECM = extracellular matrix; EM = electron microscopy; GHAP = glial hyaluronate-binding protein; GIT = gastrointestinal tract; HA = hyaluronic acid; HARE = hyaluronic acid receptor for endocytosis; HAS1, HAS2, and HAS3 = types of hyaluronan synthases 1, 2 and 3; IHABP = intracellular HA-binding protein; IMP = integral membrane protein; IL-1 = interleukine 1; LM = light microscopy; LYVE-1 = lymphatic vessel endocytic receptor; MRHD = maximum recommended human dose; NS = normal saline; OA = osteoarthrosis; P-32 = protein-32; RHAMM = receptor for hyaluronic acid mediated mobility; RHAMM/IHABP = receptor for hyaluronic acid mediated mobility/intracellular HA-binding protein; TDLo = toxic dose low; TIMP-1 = tissue inhibitor of matrix metalloproteiness 1;TNF-α = tumor necrosis factor alpha; TSG-6 = tumor necrosis factor-α-stimulated gene-6; t 1/2 = half-life; UDP = uridine diphosphate

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“…EM findings showed no significant neurotoxic findings in either group. In conclusion, epidurally-administered HA did not cause neurotoxicity in rabbits (Lim et al, 2003).…”

Section: Neurotoxicitymentioning

confidence: 67%

Hyaluronic acid (hyaluronan): a review

Nečas¹,

Bartošíková²,

Brauner³

et al. 2008

Vet. Med.

820

646

View full text Add to dashboard Cite

show abstract

“…An epidural catheter was prepared by making a knot 2.5 cm from the tip of a 17-cm microplastic catheter (PE-10; Natsume Co., Japan), as suggested previously [16,17]. The skin between T13 and L1 was incised at an approximate length of 3 cm.…”

Section: Methodsmentioning

confidence: 99%

Therapeutic Effect of Epidurally Administered Lipo-Prostaglandin E1 Agonist in a Rat Spinal Stenosis Model

et al. 2014

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BackgroundA lipo-prostaglandin E1 agonist is effective for the treatment of neurological symptoms of spinal stenosis when administered by an oral or intravenous route. we would like to reveal the therapeutic effect of an epidural injection of lipo-prostaglandin E1 on hyperalgesia in foraminal stenosis.MethodsA total of 40 male Sprague-Dawley rats were included. A small stainless steel rod was inserted into the L5/L6 intervertebral foramen to produce intervertebral foraminal stenosis and chronic compression of the dorsal root ganglia (DRG). The rats were divided into three groups: epidural PGE1 (EP) (n = 15), saline (n = 15), and control (n = 10). In the EP group, 0.15 µg.kg-1 of a lipo-PGE1 agonist was injected daily via an epidural catheter for 10 days from postoperative day 3. In the saline group, saline was injected. Behavioral tests for mechanical hyperalgesia were performed for 3 weeks. Then, the target DRG was analyzed for the degree of chromatolysis, chronic inflammation, and fibrosis in light microscopic images.ResultsFrom the fifth day after lipo-PGE1 agonist injection, the EP group showed significant recovery from mechanical hyperalgesia, which was maintained for 3 weeks (P < 0.05). Microscopic analysis showed much less chromatolysis in the EP group than in the saline or control groups.ConclusionsAn epidurally administered lipo-PGE1 agonist relieved neuropathic pain, such as mechanical hyperalgesia, in a rat foraminal stenosis model, with decreasing chromatolysis in target DRG. We suggest that epidurally administered lipo-PGE1 may be a useful therapeutic candidate for patients with spinal stenosis.

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“…According to conventional tissue sample preparation methods, the fixed tissues were made as paraffin blocks, and 4-5 µm thick sections were prepared for the slides. Primarily, Hematoxylineosin staining was performed to assess general histopathologic findings; then, four neurotoxicity categories were assessed, as previously reported: ① vacuolization of the dorsal funiculus, ② chromatolysis of the motor neuron in the ventral horn, ③ neuritis, and ④ meningeal inflammation [18,22-24]. Among them, the vacuolization of the dorsal funiculus was subdivided into 4 grades: grade 0 = no vacuole, grade 1 = vacuoles observed in less than 10% of the dorsal funiculus surface, grade 2 = vacuoles observed in 10-50% of the surface, and grade 3 = vacuoles observed in more than 50% of the surface.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of the neurological safety of epidurally-administered pregabalin in rats

Lee

Choe

et al. 2012

Korean J Anesthesiol

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BackgroundThe primary site of action of pregabalin, i.e. the α-2-δ subunit of the voltage-dependent calcium channel, is located at the dorsal root ganglion and dorsal horn of the spinal cord. Therefore, the epidural administration of pregabalin could have advantages over oral administration. However, the possibility of its neurotoxicity should be excluded before any attempt at epidural administration. We evaluated the neuronal safety of epidurally-administered pregabalin by observing the sensory/motor changes and examining the histopathology of spinal cord in rats.MethodsSixty rats of 180-230 g were divided into three groups; 3 mg of pregabalin dissolved in 0.3 ml saline (group P, n = 20), 0.3 ml 40% alcohol (group A, n = 20), or 0.3 ml normal saline (group N, n = 20) was administered epidurally to the rats in each group. Pinch-toe test, motor function evaluation, and histopathologic examination of vacuolation, chromatolysis, meningeal inflammation, and neuritis were performed at the 1st, 3rd, 7th, and 21st day after each epidural administration.ResultsAll rats enrolled in group P, like those in group N, showed neither sensory/motor dysfunction nor any histopathological abnormality over the 3-week observation period. In contrast, in group A, 80% of the rats showed abnormal response to the pinch-toe test and all rats showed decreased motor function during the entire evaluation period. In addition, all histopathologic findings of neurotoxicity were observed exclusively in group A.ConclusionsThe epidurally administered pregabalin (about 15 mg/kg) did not cause any neurotoxic evidence, in terms of both sensory/motor function evaluation and histopathological examination in rats.

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The Neurotoxicity of Epidural Hyaluronic Acid in Rabbits: A Light and Electron Microscopic Examination

Abstract: We performed a pre-clinical trial evaluation on the neurotoxicity of hyaluronic acid administered epidurally by light microscopy and electron microscopy in rabbits. Epidurally-administered hyaluronic acid did not produce any sign of neurotoxicity in rabbits.

Cited by 14 publications

References 10 publications

Hyaluronic acid (hyaluronan): a review

Hyaluronic acid (hyaluronan): a review

Therapeutic Effect of Epidurally Administered Lipo-Prostaglandin E1 Agonist in a Rat Spinal Stenosis Model

Evaluation of the neurological safety of epidurally-administered pregabalin in rats

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