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Original Article |

Nimodipine and Acceleration of Functional Recovery of the Facial Nerve After Crush Injury FREE

Robin W. Lindsay, MD; James T. Heaton, PhD; Colin Edwards, BA; Christopher Smitson, BS; Tessa A. Hadlock, MD
[+] Author Affiliations

Author Affiliations: Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston (Drs Lindsay and Hadlock and Mssrs Edwards and Smitson), Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston (Dr Heaton); and Department of Otolaryngology–Head and Neck Surgery, National Naval Medical Center, Bethesda, Maryland (Dr Lindsay).


Arch Facial Plast Surg. 2010;12(1):49-52. doi:10.1001/archfacial.2009.95.
Text Size: A A A
Published online

Objective  To establish whether nimodipine, a calcium channel blocker, accelerates or otherwise improves functional recovery of whisking after facial nerve crush injury in the rat.

Methods  Thirty rats underwent exposure of the left main trunk of the facial nerve followed by a standard crush injury and subsequent quantitative facial movement testing. Animals were randomized into an experimental group (n = 15) and a control group (n = 15). Four days prior to facial nerve manipulation, experimental animals underwent subcutaneous implantation of a nimodipine-secreting pellet. All animals were tested preoperatively and on postoperative days 2, 8 to 17, 20, 22, 24, and 31 using a validated, quantitative whisking kinematics apparatus. Whisks were analyzed for amplitude, velocity, and acceleration.

Results  Animals receiving nimodipine demonstrated significantly better whisking on 5 days (postoperative days 9, 11 to 13, and 20) compared with control animals (< .001,  = .003,  = .009,  = .009, and  = .009, respectively; 1-tailed ttest). Overall, the nimodipine-treated animals showed earlier recovery compared with the untreated animals.

Conclusions  We demonstrate that nimodipine improves recovery of whisking after facial nerve crush. This finding corroborates the semiquantitative findings of others, and provides complete whisking kinematic data on its effects. Given the low adverse effect profile of nimodipine, there may be clinical implications in its administration in patients experiencing facial nerve injury.

Figures in this Article

Facial nerve injury carries clinically significant adverse social and functional consequences, including decreased ability to communicate using facial expression, synkinesis, incomplete eye closure, external nasal valve collapse, and oral incompetence. Our laboratory is focused on the development and study of interventions designed to accelerate and improve recovery from these sequelae.

A variety of pharmacologic agents, including FK-506,1 Toki-shakuyaku-san (TJ-23),2 angiotensin II,3 and nitric oxide4,5 have been shown to improve the functional recovery of peripheral nerves after injury; however, none are in clinical use. Nimodipine, a calcium channel blocker, is a US Food and Drug Administration (FDA)- approved drug used to reduce the morbidity and mortality associated with delayed ischemic deficits in patients with subarachnoid hemorrhage. In addition to its activity in the central nervous system, nimodipine has shown promise in multiple rodent models as a possible pharmacologic treatment for peripheral nerve injury.69

Many researchers have used qualitative and semiquantitative methods to examine functional recovery of the facial nerve after injury1,10,11 and/or electrophysiologic and histomorphometric analysis to measure neural regeneration. However, electrophysiologic and histomorphometric characteristics do not necessarily correlate with functional recovery, making quantitative functional analysis the benchmark for successful reinnervation, demonstrating not only that the nerve has regenerated but also that the nerve has made appropriate end organ connections.12 We recently developed a quantitative system to measure the return of facial nerve function after injury in a rat model.13,14 This apparatus accurately measures the amplitude, velocity, and acceleration of whisks and provides a useful tool for precise observations of timing and completeness of facial nerve recovery after injury. We evaluated the effect of nimodipine on whisking kinematics after facial nerve crush injury, using a quantitative instrument to measure functional recovery. We hypothesized that treatment with nimodipine would accelerate and/or improve overall recovery from facial nerve crush compared with controls. If effective, nimodipine might provide a clinically useful treatment for facial nerve crush injuries.

HEAD FIXATION AND BEHAVIORAL ADAPTION

Thirty female Wistar-Hannover rats (Charles River Laboratories, Wilmington, Massachusetts), weighing 200 to 250 g, were handled daily for 2 weeks prior to surgery to condition them for behavior testing. Subsequently, the rats underwent surgical insertion of a light-weight titanium head implant that provided a set of 4 external attachment points for rigid head fixation, as previously described.13,14 One week after head-fixation device implantation, the rats were conditioned to a body restraint apparatus by brief daily placements into a snugly fitting sack. In the third week, a head restraint was added to the daily conditioning regimen. After the third week, the rats were sufficiently conditioned to undergo head and body restraint without struggling or showing signs of stress, and baseline testing was performed. All experimentation was conducted under protocols approved by the Massachusetts Eye and Ear Infirmary Animal Care and Use Committee and conducted in accordance with international standards on animal welfare as well as local and national regulations.

TREATMENT AND SURGERY

Animals were randomized into experimental (n = 15) and control groups (n = 15). Four days prior to facial nerve injury, the experimental animals were implanted with a subcutaneous pellet of nimodipine15 (n = 15) (40-mg, 21-day sustained-release pellet; Innovative Research of America, Sarasota, Florida). Forty-milligram pellets have been shown to provide a sustained plasma concentration of 15 ng/mL in the rat and have been safely used in other studies. In humans, a therapeutic dose of nimodipine is 7 nL/mg for the treatment of subarachnoid hemorrhage. Thus, our dose was calculated as a safe dose that maximized the plasma concentration in rats in an attempt to achieve a therapeutic effect.16,17

Rats were anesthetized with an intramuscular injection of ketamine hydrochloride, 50 mg/kg (Fort Dodge Animal Health, Fort Dodge, Iowa), and dexadetomidine hydrochloride, 0.25 mg/kg (Orion Corp, Espoo, Finland), mixed in normal saline. The left infra-auricular area was shaved and sterilely prepared. Left facial nerve exposure involved a preauricular incision, reflection of the parotid gland, and visual identification of the main trunk of the facial nerve as it emerged anteriorly to the posterior belly of the digastric muscle. The common trunk was electrically stimulated with a nerve stimulator (Montgomery Nerve Stimulator; Boston Medical Products, Westford, Massachusetts) at a setting of 1 mV to verify complete hemifacial movement. The nerve was then crushed for 30 seconds using a jeweler's microforceps, and the crush injury was repeated for an additional 30 seconds in the same location.18 The loss of electrical conductivity was verified by stimulating the proximal nerve at a setting of 2 mV and observing an absence of facial movement. The wound was closed, and the anesthetic was reversed with a subcutaneous injection of atipamezole hydrochloride, 0.05 mg/kg (Orion Corp). Rats were allowed to recover on a warming pad and were monitored postoperatively for signs of discomfort, including changes in grooming, social interaction, and for maintenance of normal body weight.

FUNCTIONAL RECOVERY TESTING

Baseline whisking testing was performed preoperatively and on postoperative day 2. Daily postoperative testing of the animals began on day 8 and continued through day 17, with additional testing on days 20, 22, 24, and 31. Whisking recovery was measured using our previously described testing apparatus.13,14 Briefly, on the day of testing, animals were placed in the body restraint device, their right and left C-1 whiskers were marked using polyimide tubes (Small Parts Inc, Miramar, Florida), and placed into the monitoring apparatus. The horizontal movement of the marked C-1 whiskers was independently tracked using commercial laser micrometers (MetraLight, Santa Mateo, California) and a data acquisition computer.14 A computer-controlled air valve was used to deliver 10-second sustained flows of scented air toward the snout to elicit whisking behavior at 2 random time points during each 5-minute data recording session per animal.

STATISTICAL ANALYSIS

The 3 largest amplitude whisks were detected and analyzed in an automated fashion for each rat on each day of recording using software adapted from Bermejo et al.19,20 The data were normalized within each animal across the 2 sides of the face by dividing the amplitude on the injured side by the amplitude on the uninjured side, giving the relative recovery of function. This is based on prior kinematic analysis by Bermejo et al19,20 and Gao et al21 that confirmed symmetric whisking in head-fixed animals. In addition, this will account for the behavioral changes in whisking effort seen with repeated testing. A group average for relative recovery of amplitude was calculated for each testing day. Independent 2-sample, 1-tailed t tests were then performed for postoperative days 8 to 17, 20, 22, 24, and 31 between the experiment group and the control group. The same data analysis was performed for the 3 whisks with the largest velocity and the 3 whisks with the greatest acceleration for postoperative days 10 to 14, the anticipated window of accelerated recovery.

All animals in both groups exhibited normal cage behavior throughout the study. They had normal weight gain and did not exhibit aggressive behavior. There were no postoperative wound infections after the head mount, pellet implantation, or facial nerve crush procedures. One animal in the control group did not become conditioned appropriately to the testing apparatus and was therefore not tested and not included in the study. All other animals tolerated testing throughout the duration of the study. No increased morbidity was noted in the drug treatment group.

On preoperative testing, the experimental and control animals demonstrated symmetric whisking with a relative amplitude of 1.00 (SE, 0.023) and 1.08 (SE, 0.025), respectively. All animals had absence of whisking function on postoperative day 2 with a relative amplitude in the experimental group of 0.09 (SE, 0.011) and a relative amplitude in the control group of 0.04 (SE, 0.013). Animals were noted to have return of whisking function starting on postoperative day 9. Return of function followed a sigmoid curve, with rapid recovery of function between postoperative days 11 and 17. The mean amplitude, velocity, and acceleration were calculated for each group. The nimodipine-treated group showed a statistically significant improvement in amplitude on days 9, 11 to 13, and 20 compared with the controls (< .001, P=.003,  = .009,  = .009, and  = .009, respectively; 1-tailed t test). A plateau of recovery was achieved between postoperative days 17 and 31, as expected. At postoperative day 31, both groups continued to demonstrate a statistically significant difference in amplitude between the operated and nonoperated sides (P = .009; 1-tailed t test) (Figure 1). The nimodipine-treated group also showed significantly better whisking velocity on days 11 to 13 and acceleration on days 11 to 14 compared with the controls (P = .007, P=.006, and  = .01, respectively for velocity and  = .007,  = .006,  = .01, and  = .03 on respective days for acceleration; 1-tailed t test) (Figure 2).

Place holder to copy figure label and caption
Figure 1.

Relative recovery of whisking amplitude over time. Relative recovery was calculated by dividing the value on the injured side by the value on the uninjured side (1 = complete recovery). Curves represent the calculated average relative amplitude of the 3 largest amplitude whisks for each animal on each day of testing. The nimodipine-treated group showed a statistically significant improvement on postoperative days 9, 11 to 13, and 20 compared with controls (P < .05; 1-tailed t test). Error bars indicate 2-tailed SE.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

The relative recovery of facial function for postoperative days 10 to 14, the days of rapid recovery of function. Relative recovery was calculated by dividing the value on the injured side by the value on the uninjured side (1 = complete recovery). The nimodipine-treated group showed a statistically significant improvement in relative amplitude on days 11 to 13 compared with the controls (P < .05; 1-tailed t test) (A). The nimodipine-treated group also showed significantly better relative whisking velocity on days 11 to 13 (B) and relative acceleration on days 11 to 14 (C) compared with the controls (P < .05; 1-tailed t test). Error bars indicate 2-tailed SE.

Graphic Jump Location

In this study, we administered nimodipine to facial nerve-crushed rodents, under the hypothesis that it would improve functional recovery. This hypothesis was based on literature showing that nimodipine, a calcium channel antagonist, improves the electrophysiologi c recovery of the recurrent laryngeal nerve and the functional recovery of the sciatic nerve after peripheral nerve crush.7,22 This study corroborates the previously reported benefits of nimodipine in peripheral nerve recovery and provides quantitative functional data that demonstrate a statistically significant improvement in the relative recovery of whisking amplitude, velocity, and acceleration during the period of rapid recovery after facial nerve crush injury.

Nimodipine has demonstrated a functional benefit after both nerve crush and nerve transection or repair; however, to our knowledge, functional analysis after extracranial facial nerve crush injury has not been previously studied. After sciatic nerve crush injury, nimodipine leads to earlier onset of functional recovery in a dose-dependent manner.22 This hastening of recovery by approximately 1 to 2 days after nimodipine treatment in the sciatic nerve is similar to our present findings in the facial nerve. In the rat laryngeal nerve, improved neuromuscular function has also been reported after nimodipine administration.7 In a case report, nimodipine was thought to improve vocal cord function after transection and repair of the recurrent laryngeal nerve.23 Nimodipine has also been shown in an intracranial facial nerve transection and repair model to decrease neuronal cell death,8 and in a peripheral nerve transection and repair model to increase axonal sprouting and decrease the polyneuronal innervation of target muscles6; however, functional analysis was not performed. In an intracranial facial nerve crush model, nimodipine did not attenuate the modest (13%) facial motor nucleus cell loss caused by axonotmesis but did accelerate the onset of axonal growth and functional recovery.9 Visual assessment of whisking after intracranial facial nerve crush identified the initiation of movement as occurring approximately 6 days sooner for nimodipine-treated rats than for controls. This more pronounced hastening of whisking recovery than found in the present report may be due to differences between intracranial vs extracranial nerve crush locations in regeneration length from the point of injury and cellular milieu at the point of injury.

Investigators15,16,24 have previously shown in rats that subcutaneous pellet administration of nimodipine is safe, enhances spatial learning, and decreases the age-related decline in performance on behavioral tasks. These studies also proved the effectiveness of subcutaneous nimodipine pellets in providing dose-dependent levels of nimodipine in both plasma and the brain.15,16 Because subcutaneous pellets obviate daily drug injections, they reduce the neurophysiological trauma that can be detrimental to behavioral testing15 and eliminate the intake and bioavailability issues associated with oral dosing regimens.17

Nimodipine acts by blocking L-type voltage-gated calcium channels; however, the precise mechanism of action by which nimodipine exerts its neuroprotective effects is still unknown. It has been theorized that it may enhance the supply of oxygen and nutrients to the injured region.22 Other experiments indicate that nimodipine may act by blocking L-type calcium channels to prevent intracellar accumulation of calcium, which leads to cell death.6 In addition, it may exert a positive affect on the calcium levels in nerve growth cones, increasing axonal spouting.9

Nimodipine is an FDA-approved, orally available drug with a low adverse effect profile. It is the only available therapy to treat subarachnoid hemorrhage-associated vasospasm and has been proven to reduce the morbidity and mortality associated with delayed ischemic deficits.25 Recently, vasoactive treatment, utilizing the prophylactic use of nimodipine in combination with hydroxyetheylsatarch, was shown to improve hearing preservation after acoustic neuroma surgery, an effect thought to be secondary to improved microcirculation.26,27 In addition, it was noted that on withdrawal of hydroxyetheylsatarch and nimodipine, patients with acoustic neuroma developed a delayed-onset facial paralysis.28,29 Thus, future work could be aimed at comparing facial nerve outcomes in patients with acoustic neuroma who were and were not treated with nimodipine for hearing preservation. Aside from nimodipine, there is no other pharmacologic treatment shown to improve facial nerve function after injury in an animal model that is safe for routine clinical use. Herein, we demonstrate a statistically significant functional improvement after facial nerve crush injury. Given that nimodipine is an FDA-approved drug with a low adverse effect profile, this represents a critical step in bringing us closer to a clinical treatment for patients after peripheral nerve crush.

In conclusion, the present study demonstrates accelerated functional recovery associated with nimodipine treatment after facial nerve crush injury. These results are consistent with prior findings of enhanced peripheral nerve recovery in rats and further indicate that nimodipine treatment may have clinical utility for patients after facial nerve injury including after acoustic neuroma surgery.

Correspondence: Robin W. Lindsay, MD, Division of Otolaryngology–Head and Neck Surgery, National Naval Medical Center, 8901 Wisconsin Ave, Bethesda, MD 20889-5600 (robin_lindsay@meei.harvard.edu).

Accepted for Publication: September 15, 2009.

Author Contributions: Drs Lindsay and Hadlock had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Lindsay, Heaton, Smitson, Edwards, and Hadlock. Acquisition of data: Lindsay, Smitson, and Edwards. Analysis and interpretation of data: Lindsay, Heaton, Smitson, and Edwards. Drafting of the manuscript: Lindsay. Critical revision of the manuscript for important intellectual content: Heaton, Smitson, Edwards, and Hadlock. Statistical analysis: Lindsay, Heaton, Smitson, and Edwards. Obtained funding: Hadlock. Administrative, technical, and material support: Hadlock. Study supervision: Hadlock.

Financial Disclosure: None reported.

Funding/Support: This study was supported by National Institutes of Health grant K-08 DEO15665-01 A2.

Yeh  CBowers  DHadlock  TA Effect of FK506 on functional recovery after facial nerve injury in the rat. Arch Facial Plast Surg 2007;9 (5) 333- 339
PubMed Link to Article
Ito  MOhbayashi  MFurukawa  MOkoyama  S Neuroprotective effects of TJ-23 (Tokishakuyakusan) on adult rat motoneurons following peripheral facial nerve axotomy. Otolaryngol Head Neck Surg 2007;136 (2) 225- 230
PubMed Link to Article
Reinecke  KLucius  RReinecke  ARickert  UHerdegen  TUnger  T Angiotensin II accelerates functional recovery in the rat sciatic nerve in vivo: role of the AT2 receptor and the transcription factor NF-kappaB. FASEB J 2003;17 (14) 2094- 2096
PubMed
Hindley  SJuurlink  BHGysbers  JWMiddlemiss  PJHerman  MARathbone  MP Nitric oxide donors enhance neurotrophin-induced neurite outgrowth through a cGMP-dependent mechanism. J Neurosci Res 1997;47 (4) 427- 439
PubMed Link to Article
González-Hernández  TRustioni  A Nitric oxide synthase and growth-associated protein are coexpressed in primary sensory neurons after peripheral injury. J Comp Neurol 1999;404 (1) 64- 74
PubMed Link to Article
Angelov  DNNeiss  WFStreppel  MAndermahr  JMader  KStennert  E Nimodipine accelerates axonal sprouting after surgical repair of rat facial nerve. J Neurosci 1996;16 (3) 1041- 1048
PubMed
Hydman  JRemahl  SBjorck  GSvensson  MMattsson  P Nimodipine improves reinnervation and neuromuscular function after injury to the recurrent laryngeal nerve in the rat. Ann Otol Rhinol Laryngol 2007;116 (8) 623- 630
PubMed
Mattsson  PAldskogius  HSvensson  M Nimodipine-induced improved survival rate of facial motor neurons following intracranial transection of the facial nerve in the adult rat. J Neurosurg 1999;90 (4) 760- 765
PubMed Link to Article
Mattsson  PJanson  AMAldskogius  HSvensson  M Nimodipine promotes regeneration and functional recovery after intracranial facial nerve crush. J Comp Neurol 2001;437 (1) 106- 117
PubMed Link to Article
Ferri  CCMoore  FABisby  MA Effects of facial nerve injury on mouse motoneurons lacking the p75 low-affinity neurotrophin receptor. J Neurobiol 1998;34 (1) 1- 9
PubMed Link to Article
Most  SP Facial nerve recovery in bcl2 overexpression mice after crush injury. Arch Facial Plast Surg 2004;6 (2) 82- 87
PubMed Link to Article
Nichols  CMMyckatyn  TMRickman  SRFox  IKHadlock  TMackinnon  SE Choosing the correct functional assay: a comprehensive assessment of functional tests in the rat. Behav Brain Res 2005;163 (2) 143- 158
PubMed Link to Article
Hadlock  TKowaleski  JLo  D  et al.  Functional assessments of the rodent facial nerve: a synkinesis model. Laryngoscope 2008;118 (10) 1744- 1749
PubMed Link to Article
Heaton  JTKowaleski  JMBermejo  RZeigler  HPAhlgren  DJHadlock  TA A system for studying facial nerve function in rats through simultaneous bilateral monitoring of eyelid and whisker movements. J Neurosci Methods 2008;171 (2) 197- 206
PubMed Link to Article
McMonagle-Strucko  KFanelli  RJ Enhanced acquisition of reversal training in a spatial learning task in rats treated with chronic nimodipine. Pharmacol Biochem Behav 1993;44 (4) 827- 835
PubMed Link to Article
Kusztos  RDIngram  DKSpangler  ELLondon  ED Effects of aging and chronic nimodipine on hippocampal binding of [3H]CGS 19755. Neurobiol Aging 1996;17 (3) 453- 457
PubMed Link to Article
Laslo  AMEastwood  JDUrquhart  BLee  TYFreeman  D Subcutaneous administration of nimodipine improves bioavailability in rabbits. J Neurosci Methods 2004;139 (2) 195- 201
PubMed Link to Article
Bridge  PMBall  DJMackinnon  SE  et al.  Nerve crush injuries: a model for axonotmesis. Exp Neurol 1994;127 (2) 284- 290
PubMed Link to Article
Bermejo  RVyas  AZeigler  HP Topography of rodent whisking, I: two-dimensional monitoring of whisker movements. Somatosens Mot Res 2002;19 (4) 341- 346
PubMed Link to Article
Bermejo  RHouben  DZeigler  HP Optoelectronic monitoring of individual whisker movements in rats. J Neurosci Methods 1998;83 (2) 89- 96
PubMed Link to Article
Gao  PBermejo  RZeigler  HP Whisker deafferentation and rodent whisking patterns. J Neurosci 2001;21 (14) 5374- 5380
PubMed
van der Zee  CESchuurman  TTraber  JGispen  WH Oral administration of nimodipine accelerates functional recovery following peripheral nerve damage in the rat. Neurosci Lett 1987;83 (1-2) 143- 148
PubMed Link to Article
Mattsson  PBjorck  GRemahl  S  et al.  Nimodipine and microsurgery induced recovery of the vocal cord after recurrent laryngeal nerve resection. Laryngoscope 2005;115 (10) 1863- 1865
PubMed Link to Article
Ingram  DKJoseph  JASpangler  ELRoberts  DHengemihle  JFanelli  RJ Chronic nimodipine treatment in aged rats. Neurobiol Aging 1994;15 (1) 55- 61
PubMed Link to Article
Allen  GSAhn  HSPreziosi  TJ  et al.  Cerebral arterial spasm. N Engl J Med 1983;308 (11) 619- 624
PubMed Link to Article
Strauss  CBischoff  BNeu  MBerg  MFahlbusch  RRomstock  J Vasoactive treatment for hearing preservation in acoustic neuroma surgery. J Neurosurg 2001;95 (5) 771- 777
PubMed Link to Article
Strauss  CBischoff  BRomstock  JRachinger  JRampp  SPrell  J Hearing preservation in medial vestibular schwannomas. J Neurosurg 2008;109 (1) 70- 76
PubMed Link to Article
Scheller  CRichter  HPEngelhardt  MKoenig  RAntoniadis  G The influence of prophylactic vasoactive treatment on cochlear and facial nerve functions after vestibular schwannoma surgery: a prospective and open-label randomized pilot study. Neurosurgery 2007;61 (1) 92- 98
PubMed Link to Article
Scheller  CStrauss  CFahlbusch  RRomstock  J Delayed facial nerve paresis following acoustic neuroma resection and postoperative vasoactive treatment. Zentralbl Neurochir 2004;65 (3) 103- 107
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Relative recovery of whisking amplitude over time. Relative recovery was calculated by dividing the value on the injured side by the value on the uninjured side (1 = complete recovery). Curves represent the calculated average relative amplitude of the 3 largest amplitude whisks for each animal on each day of testing. The nimodipine-treated group showed a statistically significant improvement on postoperative days 9, 11 to 13, and 20 compared with controls (P < .05; 1-tailed t test). Error bars indicate 2-tailed SE.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

The relative recovery of facial function for postoperative days 10 to 14, the days of rapid recovery of function. Relative recovery was calculated by dividing the value on the injured side by the value on the uninjured side (1 = complete recovery). The nimodipine-treated group showed a statistically significant improvement in relative amplitude on days 11 to 13 compared with the controls (P < .05; 1-tailed t test) (A). The nimodipine-treated group also showed significantly better relative whisking velocity on days 11 to 13 (B) and relative acceleration on days 11 to 14 (C) compared with the controls (P < .05; 1-tailed t test). Error bars indicate 2-tailed SE.

Graphic Jump Location

Tables

References

Yeh  CBowers  DHadlock  TA Effect of FK506 on functional recovery after facial nerve injury in the rat. Arch Facial Plast Surg 2007;9 (5) 333- 339
PubMed Link to Article
Ito  MOhbayashi  MFurukawa  MOkoyama  S Neuroprotective effects of TJ-23 (Tokishakuyakusan) on adult rat motoneurons following peripheral facial nerve axotomy. Otolaryngol Head Neck Surg 2007;136 (2) 225- 230
PubMed Link to Article
Reinecke  KLucius  RReinecke  ARickert  UHerdegen  TUnger  T Angiotensin II accelerates functional recovery in the rat sciatic nerve in vivo: role of the AT2 receptor and the transcription factor NF-kappaB. FASEB J 2003;17 (14) 2094- 2096
PubMed
Hindley  SJuurlink  BHGysbers  JWMiddlemiss  PJHerman  MARathbone  MP Nitric oxide donors enhance neurotrophin-induced neurite outgrowth through a cGMP-dependent mechanism. J Neurosci Res 1997;47 (4) 427- 439
PubMed Link to Article
González-Hernández  TRustioni  A Nitric oxide synthase and growth-associated protein are coexpressed in primary sensory neurons after peripheral injury. J Comp Neurol 1999;404 (1) 64- 74
PubMed Link to Article
Angelov  DNNeiss  WFStreppel  MAndermahr  JMader  KStennert  E Nimodipine accelerates axonal sprouting after surgical repair of rat facial nerve. J Neurosci 1996;16 (3) 1041- 1048
PubMed
Hydman  JRemahl  SBjorck  GSvensson  MMattsson  P Nimodipine improves reinnervation and neuromuscular function after injury to the recurrent laryngeal nerve in the rat. Ann Otol Rhinol Laryngol 2007;116 (8) 623- 630
PubMed
Mattsson  PAldskogius  HSvensson  M Nimodipine-induced improved survival rate of facial motor neurons following intracranial transection of the facial nerve in the adult rat. J Neurosurg 1999;90 (4) 760- 765
PubMed Link to Article
Mattsson  PJanson  AMAldskogius  HSvensson  M Nimodipine promotes regeneration and functional recovery after intracranial facial nerve crush. J Comp Neurol 2001;437 (1) 106- 117
PubMed Link to Article
Ferri  CCMoore  FABisby  MA Effects of facial nerve injury on mouse motoneurons lacking the p75 low-affinity neurotrophin receptor. J Neurobiol 1998;34 (1) 1- 9
PubMed Link to Article
Most  SP Facial nerve recovery in bcl2 overexpression mice after crush injury. Arch Facial Plast Surg 2004;6 (2) 82- 87
PubMed Link to Article
Nichols  CMMyckatyn  TMRickman  SRFox  IKHadlock  TMackinnon  SE Choosing the correct functional assay: a comprehensive assessment of functional tests in the rat. Behav Brain Res 2005;163 (2) 143- 158
PubMed Link to Article
Hadlock  TKowaleski  JLo  D  et al.  Functional assessments of the rodent facial nerve: a synkinesis model. Laryngoscope 2008;118 (10) 1744- 1749
PubMed Link to Article
Heaton  JTKowaleski  JMBermejo  RZeigler  HPAhlgren  DJHadlock  TA A system for studying facial nerve function in rats through simultaneous bilateral monitoring of eyelid and whisker movements. J Neurosci Methods 2008;171 (2) 197- 206
PubMed Link to Article
McMonagle-Strucko  KFanelli  RJ Enhanced acquisition of reversal training in a spatial learning task in rats treated with chronic nimodipine. Pharmacol Biochem Behav 1993;44 (4) 827- 835
PubMed Link to Article
Kusztos  RDIngram  DKSpangler  ELLondon  ED Effects of aging and chronic nimodipine on hippocampal binding of [3H]CGS 19755. Neurobiol Aging 1996;17 (3) 453- 457
PubMed Link to Article
Laslo  AMEastwood  JDUrquhart  BLee  TYFreeman  D Subcutaneous administration of nimodipine improves bioavailability in rabbits. J Neurosci Methods 2004;139 (2) 195- 201
PubMed Link to Article
Bridge  PMBall  DJMackinnon  SE  et al.  Nerve crush injuries: a model for axonotmesis. Exp Neurol 1994;127 (2) 284- 290
PubMed Link to Article
Bermejo  RVyas  AZeigler  HP Topography of rodent whisking, I: two-dimensional monitoring of whisker movements. Somatosens Mot Res 2002;19 (4) 341- 346
PubMed Link to Article
Bermejo  RHouben  DZeigler  HP Optoelectronic monitoring of individual whisker movements in rats. J Neurosci Methods 1998;83 (2) 89- 96
PubMed Link to Article
Gao  PBermejo  RZeigler  HP Whisker deafferentation and rodent whisking patterns. J Neurosci 2001;21 (14) 5374- 5380
PubMed
van der Zee  CESchuurman  TTraber  JGispen  WH Oral administration of nimodipine accelerates functional recovery following peripheral nerve damage in the rat. Neurosci Lett 1987;83 (1-2) 143- 148
PubMed Link to Article
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