Acute Phase Effect of Memantine Hydrochloride in Experimental Peripheral Nerve Injury

Abstract

Aim In this experimental study, we aimed to investigate possible healing effects of memantine hydrochloride, an N-methyl-d-aspartate (NMDA) antagonist, with clinical, biochemical, and histopathologic methods on acute peripheral nerve injury (PNI).

Material and Method Forty-eight adult Wistar albino rats were divided into four groups (n = 12). The groups were arranged as sham-operated group (group 1), acute compression model group (group 2), trauma + low-dose memantine group (group 3), and trauma + high-dose memantine group (group 4). Memantine was administered intraperitoneally for 7 days. Subjects were sacrificed after the measurement of the sciatic nerve function index (SNFI) on the eighth day. Cyclooxygenase 2 (COX-2) and tumor necrosis factor-α (TNF-α) levels were measured in nerve tissues. Histopathologic evaluation was performed by electron microscopy.

Results The mean sciatic function index (SFI) scores of groups 1 to 4 were +3.27 (standard deviation [SD] ±4.66),–18.2 (SD = ±11.7),–8.5 (SD = ±7.5), and–2.5 (SD = ±9), respectively. The mean COX-2 values were 0.98 ng/mL (SD = ±0.51), 1.89 ng/mL (SD = ±0.22), 1.39 ng/mL (SD = ±0.36), and 1.35 ng/mL (SD = ±0.59), respectively. TNF-α values were 0.09 pg/mL (SD = ±0.23), 1 pg/mL (SD = ±0.96), 0.46 pg/mL (SD = ±0.55), and 0.48 pg/mL (SD = ±0.78), respectively. Group 1 showed normal histologic findings. Group 2 showed marked edema particularly in large-diameter myelins. Myelin configurations were detected in large myelinated axons in group 3. The number of mast cells in endoneurium was high in group 4.

Conclusion The efficacy of memantine in the acute phase of PNI appears to be significant according to the SNFI and biochemical tests. However, histologic findings suggest that high doses of memantine have a negative effect on PNI.

Keywords

peripheral nerve injury - memantine - cyclooxygenase-2

• References

• 1 Robinson LR. Traumatic injury to peripheral nerves. Muscle Nerve 2000; 23 (06) 863-873
• 2 Burnett MG, Zager EL. Pathophysiology of peripheral nerve injury: a brief review. Neurosurg Focus 2004; 16 (05) E1
• 3 Frostick SP, Yin Q, Kemp GJ. Schwann cells, neurotrophic factors, and peripheral nerve regeneration. Microsurgery 1998; 18 (07) 397-405
• 4 Pagnotta A, Tos P, Fornaro M, Gigante A, Geuna S, Battiston B. Neurotrophins and their receptors in early axonal regeneration along muscle-vein-combined grafts. Microsurgery 2002; 22 (07) 300-303
• 5 Melcangi RC, Cavarretta IT, Ballabio M. et al. Peripheral nerves: a target for the action of neuroactive steroids. Brain Res Brain Res Rev 2005; 48 (02) 328-338
• 6 Marcolino AM, Barbosa RI, Neves LMS. et al. Low intensity laser (830 nm) functional to recover of the sciatic nerve in rats. Acta Ortop Bras 2010; 18 (04) 207-211
• 7 Morani AS, Bodhankar SL. Neuroprotective effect of vitamin E acetate in models of mononeuropathy in rats. Neuroanatomy 2008; 7: 33-37
• 8 Seeman P, Caruso C, Lasaga M. Memantine agonist action at dopamine D2 high receptors. Synapse 2008; 62 (02) 149-153
• 9 Buvanendran A, Kroin JS. Early use of memantine for neuropathic pain. Anesth Analg 2008; 107 (04) 1093-1094
• 10 Park BY, Park SH, Kim WM. et al. Antinociceptive effect of memantine and morphine on vincristine-induced peripheral neuropathy in rats. Korean J Pain 2010; 23 (03) 179-185
• 11 Chipana C, Camarasa J, Pubill D, Escubedo E. Memantine prevents MDMA-induced neurotoxicity. Neurotoxicology 2008; 29 (01) 179-183
• 12 Sang CN, Booher S, Gilron I, Parada S, Max MB. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials. Anesthesiology 2002; 96 (05) 1053-1061
• 13 Ghayour M-B, Abdolmaleki A, Behnam-Rassouli M. The effect of memantine on functional recovery of the sciatic nerve crush injury in rats. Turk Neurosurg 2017; 27 (04) 641-647
• 14 Scopel GP, Faria JCM, Busnardo FF, Alves HRN, Orpheu SC, Ferreira MC. Experimental intraneural hematoma model in rats: evaluation of functional recovery and neural histomorphometry. Acta Ortop Bras 2007; 15 (04) 222-226
• 15 Omura T, Sano M, Omura K, Hasegawa T, Nagano A. A mild acute compression induces neurapraxia in rat sciatic nerve. Int. J Neurosci 2004; 114 (12) 1561-1572
• 16 Andrews FJ. Retroperitoneal haematoma after paracetamol increased anticoagulation. Emerg Med J 2002; 19 (01) 84-85
• 17 Elesber AA, Kent PD, Jennings CA. Compressive neuropathy of the brachial plexus and long thoracic nerve: a rare complication of heparin anticoagulation. Chest 2001; 120 (01) 309-311
• 18 Makwana M, Raivich G. Molecular mechanisms in successful peripheral regeneration. FEBS J 2005; 272 (11) 2628-2638
• 19 Kalender AM, Doğan A, Bakan V, Yildiz H, Gökalp MA, Kalender M. Effect of Zofenopril on regeneration of sciatic nerve crush injury in a rat model. J Brachial Plex Peripher Nerve Inj 2009; 4: 6
• 20 Algora J, Chen L-E, Seaber AV, Wong GHW, Urbaniak JR. Functional effects of lymphotoxin on crushed peripheral nerve. Microsurgery 1996; 17 (03) 131-135
• 21 Areosa Sastre A, McShane R, Sherriff F. Memantine for dementia. Cochrane Database Syst Rev 2004; (04) CD003154
• 22 Geter-Douglass B, Witkin JM. Behavioral effects and anticonvulsant efficacies of low-affinity, uncompetitive NMDA antagonists in mice. Psychopharmacology (Berl) 1999; 146 (03) 280-289
• 23 Handforth A, Bordelon Y, Frucht SJ, Quesada A. A pilot efficacy and tolerability trial of memantine for essential tremor. Clin Neuropharmacol 2010; 33 (05) 223-226
• 24 Buvanendran A, Kroin JS. Early use of memantine for neuropathic pain. Anesth Analg 2008; 107 (04) 1093-1094
• 25 Vogels BAPM, Maas MAW, Daalhuisen J, Quack G, Chamuleau RAFM. Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats. Hepatology 1997; 25 (04) 820-827
• 26 Harvey BH, Bothma T, Nel A, Wegener G, Stein DJ. Involvement of the NMDA receptor, NO-cyclic GMP and nuclear factor K-. β. in an animal model of repeated trauma. Hum Psychopharmacol 2005; 20 (05) 367-373
• 27 Park BY, Park SH, Kim WM, Yoon MH, Lee HG. Antinociceptive effect of memantine and morphine on vincristine-induced peripheral neuropathy in rats. Korean J Pain 2010; 23 (03) 179-185
• 28 Chipana C, Camarasa J, Pubill D, Escubedo E. Memantine prevents MDMA-induced neurotoxicity. Neurotoxicology 2008; 29 (01) 179-183
• 29 Sang CN, Booher S, Gilron I, Parada S, Max MB. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials. Anesthesiology 2002; 96 (05) 1053-1061
• 30 Schifitto G, Navia BA, Yiannoutsos CT. et al. Adult AIDS Clinical Trial Group (ACTG) 301, 700 Teams, HIV MRS Consortium. Memantine and HIV-associated cognitive impairment: a neuropsychological and proton magnetic resonance spectroscopy study. AIDS 2007; 21 (14) 1877-1886
• 31 Suzuki R, Matthews EA, Dickenson AH. Comparison of the effects of MK-801, ketamine and memantine on responses of spinal dorsal horn neurones in a rat model of mononeuropathy. Pain 2001; 91 (1-2) 101-109
• 32 Chen S-R, Samoriski G, Pan H-L. Antinociceptive effects of chronic administration of uncompetitive NMDA receptor antagonists in a rat model of diabetic neuropathic pain. Neuropharmacology 2009; 57 (02) 121-126
• 33 Schley M, Topfner S, Wiech K. et al. Continuous brachial plexus blockade in combination with the NMDA receptor antagonist memantine prevents phantom pain in acute traumatic upper limb amputees. Eur J Pain 2007; 11 (03) 299-308
• 34 Wiech K, Kiefer R-T, Töpfner S. et al. A placebo-controlled randomized crossover trial of the. N . -methyl-D-aspartic acid receptor antagonist, memantine, in patients with chronic phantom limb pain. Anesth Analg 2004; 98 (02) 408-413
• 35 Nikolajsen L, Gottrup H, Kristensen AGD, Jensen TS. Memantine (a N-methyl-D-aspartate receptor antagonist) in the treatment of neuropathic pain after amputation or surgery: a randomized, double-blinded, cross-over study. Anesth Analg 2000; 91 (04) 960-966
• 36 Hackworth RJ, Tokarz KA, Fowler IM. Wallace SC, Stedje-Larsen ET. Profound pain reduction after induction of memantine treatment in two patients with severe phantom limb pain. Anesth Analg 2008; 107 (04) 1377-1379
• 37 Chaplan SR, Malmberg AB, Yaksh TL. Efficacy of spinal NMDA receptor antagonism in formalin hyperalgesia and nerve injury evoked allodynia in the rat. J Pharmacol Exp Ther 1997; 280 (02) 829-838
• 38 Cámara-Lemarroy CR, Guzmán-de la Garza FJ, Barrera-Oranday EA, Cabello-García AJ, García-Tamez A, Fernández-Garza NE. Celecoxib accelerates functional recovery after sciatic nerve crush in the rat. J Brachial Plex Peripher Nerve Inj 2008; 3 (25) 25
• 39 Bashyam H, Cerami A. Uncovering the dark side of TNF. J Exp Med 2007; 204 (09) 2013
• 40 Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 2001; 104 (04) 487-501
• 41 Sullivan KE. TNF and TNF. α. inhibitors: mechanisms of action. Pediatr Rheumatol Online J 2004; 2 (01) 7-22
• 42 Dayer J-M, Beutler B, Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med 1985; 162 (06) 2163-2168
• 43 Moldawer LL, Marano MA, Wei H. et al. Cachectin/tumor necrosis factor-. α. alters red blood cell kinetics and induces anemia in vivo. FASEB J 1989; 3 (05) 1637-1643
• 44 George A, Schmidt C, Weishaupt A, Toyka KV, Sommer C. Serial determination of tumor necrosis factor-alpha content in rat sciatic nerve after chronic constriction injury. Exp Neurol 1999; 160 (01) 124-132
• 45 La Fleur M, Underwood JL, Rappolee DA, Werb Z. Basement membrane and repair of injury to peripheral nerve: defining a potential role for macrophages, matrix metalloproteinases, and tissue inhibitor of metalloproteinases-1. J Exp Med 1996; 184 (06) 2311-2326
• 46 Corfas G, Velardez MO, Ko CP, Ratner N, Peles E. Mechanisms and roles of axon-Schwann cell interactions. J Neurosci 2004; 24 (42) 9250-9260
• 47 MF G, M M, S H. Khan WS. Peripheral nerve injury: principles for repair and regeneration. Open Orthop J 2014; 8: 199-203