Efficacy of a fixed combination of palmitoylethanolamide and acetyl-l-carnitine (PEA+ALC FC) in the treatment of neuropathies secondary to rheumatic diseases.

BACKGROUND: The neurologic complications of rheumatic diseases (RDs) are highly variable, and their manifestations are linked to the pathogenesis and clinical phenotype of the specific RDs. In rheumatoid arthritis, for example, the peripheral nervous system is most commonly involved and mononeuritis multiplex, nerve entrapment and vasculitic sensorimotor neuropathies are not uncommon. Often the therapy for these disorders is not easy and is characterized by the use of different drugs. Palmitoylethanolamide (PEA) has been tested in a wide variety of animal models and has been evaluated in several clinical studies for nerve compression syndromes, demonstrating that PEA acts as an effective and safe analgesic compound. Acetyl-L-Carnitine (ALC) has also been shown to be an effective and safe treatment in painful peripheral neuropathy. In the last years the synergistic effect between PEA and ALC has been demonstrated. The aim of our study was to evaluate the efficacy of supplementation of standard therapy (STh) with Kalanit® (Chiesi Italia Spa; Parma, Italy) in patients with peripheral neuropathy secondary to RDs. METHODS: Patients at the time of enrollment were affected by RDs with neuropathy from <12 months, documented by electromyography. The analyzed patients were treated with the STh chosen according to their rheumatic disease (RA or SpA) and for their neuropathy (e.g. analgesic, NSAIDs, pregabalin or gabapentin) as per clinical practice. The sample was divided into 2 groups: group 1, patients treated with STh, to which a fixed combination of PEA (600 mg) + ALC (500 mg) (Kalanit®) was added twice a day for 2 weeks and then once a day for 6 months; group 2, patients treated only with STh. Each patient underwent clinical evaluations and questionnaires were administered in order to evaluate their neuropathy and the efficacy of the therapy. RESULTS: In group 1, 18 patients suffering from sciatic pain, 16 patients from carpal tunnel syndrome and 8 patients with peripheral neuropathy of the lower limbs were included and PEA + ALC FC was added to STh. These patients were compared with patients from group 2, who had the same pathology and demographic characteristics: 20 patients with sciatic pain, 15 with carpal tunnel syndrome and 5 with peripheral neuropathy of the lower limbs, respectively; this group was treated with STh only. Patients treated with PEA + ALC FC had a significant improvement in pain VAS compared to patients treated with group 2 in all the diseases analyzed (P value: sciatic pain 0.032, carpal tunnel syndrome 0.025 and lower limbs neuropathy 0.041). Patients in group 1 showed a significant improvement compared to patients treated in group 2 also from a specific score. Specifically, LBP-IQ showed significant improvement in group one (P value: 0.031), as did CHFD (P=0.011) and NPQ (P=0.025). CONCLUSIONS: The synergistic effect of PEA and ALC seems to have a further advantage in the treatment of this type of pathology, including the anti-inflammatory effect but also in terms of therapy optimization and therefore of better adherence to treatments. Our study shows that it is important to identify the type of pain to follow an accurate diagnostic algorithm, considering the clinical characteristics of the patient and carefully evaluate the indication, preferring a multimodal approach.

Effect of levetiracetam versus gabapentin on peripheral neuropathy and sciatic degeneration in streptozotocin-diabetic mice: Influence on spinal microglia and astrocytes.

Peripheral diabetic neuropathy develops in diabetic patients. The current study tested the antiallodynic and antihyperalgesic effects of the anticonvulsant drug, levetiracetam compared with the standard drug, gabapentin, in a model of streptozotocin-induced peripheral diabetic neuropathy. Male albino mice were injected intraperitoneally with streptozotocin (40mg/kg) for five consecutive days to induce type 1 diabetes mellitus. After development of peripheral diabetic neuropathy, mice were then treated orally with 10 doses of levetiracetam or gabapentin (or vehicle). The effect of multiple doses of levetiracetam on the histopathology of sciatic nerve and spinal cord was tested. Furthermore, the effect of levetiracetam on the spinal expression of microglia and astrocytes was examined in comparison with gabapentin. Results indicated that the highest dose of levetiracetam and all doses of gabapentin increased the withdrawal threshold in von Frey test. Furthermore, all doses of levetiracetam and gabapentin prolonged the reaction time exhibited by diabetic mice tested in hot plate test. Both drugs provided protection for the sciatic nerve and the spinal cord. In addition, levetiracetam (20 and 40mg/kg) decreased spinal immunostaining for CD11b (microglia marker) and glial fibrillary acidic protein (GFAP, astrocytes marker) however; the high dose of gabapentin (40mg/kg) reduced the spinal immunostaining for GFAP only. In conclusion, levetiracetam produced antiallodynic and antihyperalgesic effect in diabetic mice with favorable effects on sciatic nerve and spinal cord that were accompanied by downregulation of the spinal expression of microglia and astrocytes. Thus, levetiracetam may have promise in alleviating neuropathic pain in diabetic patients.

Ameliorative potential of Ocimum sanctum in chronic constriction injury-induced neuropathic pain in rats.

The present study was designed to investigate the ameliorative potential of Ocimum sanctum and its saponin rich fraction in chronic constriction injury-induced neuropathic pain in rats. The chronic constriction injury was induced by placing four loose ligatures around the sciatic nerve, proximal to its trifurcation. The mechanical hyperalgesia, cold allodynia, paw heat hyperalgesia and cold tail hyperalgesia were assessed by performing the pinprick, acetone, hot plate and cold tail immersion tests, respectively. Biochemically, the tissue thio-barbituric acid reactive species, super-oxide anion content (markers of oxidative stress) and total calcium levels were measured. Chronic constriction injury was associated with the development of mechanical hyperalgesia, cold allodynia, heat and cold hyperalgesia along with an increase in oxidative stress and calcium levels. However, administration of Ocimum sanctum (100 and 200 mg/kg p.o.) and its saponin rich fraction (100 and 200 mg/kg p.o.) for 14 days significantly attenuated chronic constriction injury-induced neuropathic pain as well as decrease the oxidative stress and calcium levels. It may be concluded that saponin rich fraction of Ocimum sanctum has ameliorative potential in attenuating painful neuropathic state, which may be attributed to a decrease in oxidative stress and calcium levels.

Practice of yoga may cause damage of both sciatic nerves: a case report.

Sciatic nerve traumatic damage very rarely occurs bilaterally. We describe the case of a 67-year-old woman who reported a bilateral traumatic lesion of the sciatic nerve during practice of yoga. Nerve conduction studies showed a bilateral sciatic nerve neuropathy, mostly affecting the peroneal component. Lumbar plexus MRI documented regular anatomical features of the main principal nerve roots with bilateral T2 signal alteration of roots L4, L5 and S1 that extended into the sciatic nerves showing both increase in size, probably related to chronic injury of nerves, and an alteration in diffusion signal that suggested a recent acute overlapped process.

Disparate changes in the expression of transient receptor potential vanilloid type 1 receptor mRNA and protein in dorsal root ganglion neurons following local capsaicin treatment of the sciatic nerve in the rat.

In situ hybridization, quantitative reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry, and Western blot analysis were applied to study the changes in expression of the major nociceptive ion channel transient receptor potential vanilloid type 1 receptor (TRPV1) after the perineural application of capsaicin or nerve transection. In control rats, quantitative morphometric and statistical analyses of TRPV1 protein and mRNA expression in L5 dorsal root ganglion cells revealed distinct populations of small (type C) and small-to-medium (type B) neurons, which showed very high and moderate levels of TRPV1, whereas larger (type A) neurons mostly did not express this receptor. After either transection or capsaicin treatment of the sciatic nerve, immunohistochemistry and Western blotting demonstrated a massive (up to 80%) decrease in the proportion of TRPV1-immunoreactive neurons and TRPV1 protein at all postoperative survival times. In situ hybridization indicated marked decreases (up to 85%) in the proportion of neurons that expressed TRPV1 mRNA after sciatic nerve transection. In contrast, although perineural treatment with capsaicin resulted in similar substantial decreases in the proportions of type B and C neurons of the L5 dorsal root ganglia 3 days postoperatively, a clear-cut tendency to recovery was observed thereafter. Hence, the proportions of both type B and C neurons expressing TRPV1 mRNA reached up to 70% of the control levels at 30 days postoperatively. In accord with these findings, quantitative RT-PCR revealed a marked and significant recovery in TRPV1 mRNA after perineural capsaicin but not after nerve transection. These observations suggest the involvement of distinct cellular mechanisms in the regulation of the TRPV1 mRNA expression of damaged neurons, specifically triggered by the nature of the injury. The present findings imply that the antinociceptive and anti-inflammatory effects of perineurally applied capsaicin involve distinct changes in neuronal TRPV1 mRNA expression and long-lasting alterations in (post)translational regulation.

Effects of 660 and 780 nm low-level laser therapy on neuromuscular recovery after crush injury in rat sciatic nerve.

BACKGROUND AND OBJECTIVE: Post-traumatic nerve repair is still a challenge for rehabilitation. It is particularly important to develop clinical protocols to enhance nerve regeneration. The present study investigated the effects of 660 and 780 nm low-level laser therapy (LLLT) using different energy densities (10, 60, and 120 J/cm²) on neuromuscular and functional recovery as well as on matrix metalloproteinase (MMP) activity after crush injury in rat sciatic nerve. MATERIALS AND METHODS: Rats received transcutaneous LLLT irradiation at the lesion site for 10 consecutive days post-injury and were sacrificed 28 days after injury. Both the sciatic nerve and tibialis anterior muscles were analyzed. Nerve analyses consisted of histology (light microscopy) and measurements of myelin, axon, and nerve fiber cross-sectional area (CSA). S-100 labeling was used to identify myelin sheath and Schwann cells. Muscle fiber CSA and zymography were carried out to assess the degree of muscle atrophy and MMP activity, respectively. Statistical significance was set at 5% (P≤0.05). RESULTS: Six hundred sixty nanometer LLLT either using 10 or 60 J/cm² restored muscle fiber, myelin and nerve fiber CSA compared to the normal group (N). Furthermore, it increased MMP-2 activity in nerve and decreased MMP-2 activity in muscle and MMP-9 activity in nerve. In contrast, 780 nm LLLT using 10 J/cm² decreased MMP-9 activity in nerve compared to the crush group (CR) and N; it also restored normal levels of myelin and nerve fiber CSA. Both 60 and 120 J/cm² decreased MMP-2 activity in muscle compared to CR and N. 780 nm did not prevent muscle fiber atrophy. Functional recovery in the irradiated groups did not differ from the non-irradiated CR. CONCLUSION: Data suggest that 660 nm LLLT with low (10 J/cm²) or moderate (60 J/cm²) energy densities is able to accelerate neuromuscular recovery after nerve crush injury in rats.

Protective effects of the calcium-channel blocker flunarizine on crush injury of sciatic nerves in a rat model.

BACKGROUND: Neural damage can be mitigated by calcium-channel blockers (CCBs). However, the mechanism of action of CCBs is not yet fully understood. Objective : To investigate the mechanism of action and efficacy of CCB, flunarizine in restoring neural function after crush injury to the nerves. MATERIALS AND METHODS: The sciatic nerves of rats were crushed using pincers to establish the model for crush injury. Two hundred and eighty-eight Sprague-Dawley (SD) rats were randomly divided into sham-operated, saline, and low-dose flunarizine and high-dose flunarizine (FI and FII) groups. The expression of the protein c-fos in the dorsal root ganglia (DRG) after crush injury to the sciatic nerves was investigated by using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. The effect of flunarizine on c-fos expression and its efficacy in restoring neural function was evaluated. RESULTS: The c-fos messenger ribonucleic acid (mRNA) and protein expression in FI and FII groups was significantly lower than in the saline group and was the least in the FII group. Nerve-conduction velocity was increased in the order of: saline < FI< FII< sham-operated. There was no significant difference in the nerve-conduction velocity in the sham-operated and FII groups (P>.05). CONCLUSIONS: When administered after crush injury to peripheral nerves, flunarizine may protect neurons with lesions from further damage and improve neural function by downregulating c-fos expression.

Porous silicon as a potential electrode material in a nerve repair setting: Tissue reactions.

We compared porous silicon (pSi) with smooth Si as chip-implant surfaces in a nerve regeneration setting. Silicon chips can be used for recording neural activity and are potential nerve interface devices. A silicon chip with one smooth and one porous side inserted into a tube was used to bridge a 5 mm defect in rat sciatic nerve. Six or 12 weeks later, new nerve structures surrounded by a perineurium-like capsule had formed on each side of the chip. The number of regenerated nerve fibers did not differ on either side of the chip as shown by immunostaining for neurofilaments. However, the capsule that had formed in contact with the chip was significantly thinner on the porous side than on the smooth side. Cellular protrusions had formed on the pSi side and the regenerated nerve tissue was found to attach firmly to this surface, while the tissue was hardly attached to the smooth silicon surface. We conclude that a pSi surface, due to its large surface area, diminished inflammatory response and firm adhesion to the tissue, should be a good material for the development of new implantable electronic nerve devices.

Enhanced 3,5-dihydroxyphenylglycine-induced sustained nociceptive behaviors in rats with neuropathy or chronic inflammation.

Sustained nociceptive behaviors (SNBs) are an important but under-studied component of chronic pain conditions. The group I metabotropic glutamate receptor (mGluR) agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) produces SNBs when injected intrathecally, and group I mGluR antagonists are effective at reducing symptoms of neuropathic and inflammatory pain. The present experiments examined whether rats with sciatic nerve injury or persistent inflammation exhibit greater SNBs following intrathecal DHPG compared with control animals. SNBs were observed following intrathecal injection of DHPG (25 nmol) between the L4 and L5 vertebrae. We used a behavioral observation scoring system that allowed for assessment of specific behaviors in the hind paws. When DHPG was injected intrathecally in rats with chronic constriction injury (CCI) of the sciatic nerve, they showed increased paw stamping behavior compared to DHPG-injected sham controls. Rats treated with complete Freund's adjuvant (CFA)-induced inflammation failed to demonstrate a significant increase in paw stamping behavior. However, both CCI and CFA rats showed increased paw licking and biting of the neuropathic/inflamed hind paw after intrathecal DHPG injection. These results provide evidence for behaviorally relevant contributions of group I mGluRs to SNBs in models of neuropathic and inflammatory pain.

Yoga neuropathy. A snoozer.

Sciatic nerve compression very rarely occurs bilaterally. The authors present a woman with profound lower extremity weakness and sensory abnormality after falling asleep in the head-to-knees yoga position (also called "Paschimottanasana"). Clinical and electrodiagnostic findings are discussed in detail and a brief review of the literature is presented.

Effects of lumbar acupuncture stimulation on blood flow to the sciatic nerve trunk--an exploratory study.

INTRODUCTION: Acupuncture may have a role in the treatment of intermittent claudication of the cauda equina due to lumbar spinal canal stenosis. The aim of this study was to explore the possible physiological mechanisms. METHODS: In a laboratory experiment, manual acupuncture was performed at a point adjacent to the sixth lumbar vertebra of 13 animals and its effect on sciatic nerve blood flow was measured using a laser Doppler flowmetry. Simultaneously, changes in blood pressure and cardiac rate were observed. Each animal was stimulated four to eight times, making a total of 58 experiments. RESULTS: Acupuncture stimulation did not produce consistent changes in sciatic nerve blood flow, with increased and decreased blood flow as well as no change in blood flow observed. Among the 58 individual experiments, sciatic nerve blood flow was increased in 33, reduced in 12, and unchanged in 13. Approximately half of the stimulations showed a correlation between blood flow and blood pressure change. CONCLUSION: Our results indicate that lumbar acupuncture stimulation can have an influence on sciatic nerve blood flow. The effect is dependent not only on blood pressure but also other factors, for example vasodilator and vasoconstrictor nerve activity. This mechanism may contribute to a clinical effect on intermittent claudication of the cauda equina.

[Photochromotherapy of experimental compression-ischemic neuropathy]. / Fotokhromoterapiia éksperimental'noi kompressionno-ishemicheskoi nevropatii.

Effects of monochrome light of the green and red spectra (mean wave length 540 and 670 nm, respectively) were studied on experimental rat model of compression-ischemic neuropathy (40 animals). The nerve under compression was exposed to green and red light using light-diode physiotherapeutic unit "Spectr-LC" with different intensity. Electromyographic parameters of the compressed nerve improved significantly after exposure to monochrome green light with intensity 500 mJ/cm2. The effect was dose dependent. Green light produced better effect.