Nijee Sharma

Electrical stimulation and testosterone differentially enhance expression of regeneration-associated genes.

As functional recovery following peripheral nerve injury is dependent upon successful repair and regeneration, treatments that enhance different regenerative events may be advantageous. Using a rat facial nerve crush axotomy model, our lab has previously investigated the effects of a combinatorial treatment strategy, consisting of electrical stimulation (ES) of the proximal nerve stump and testosterone propionate (TP) administration. Results indicated that the two treatments differentially enhance facial nerve regenerative properties, whereby ES reduced the delay before sprout formation, TP accelerated the overall regeneration rate, and the combinatorial treatment had additive effects. To delineate the molecular mechanisms underlying such treatments, the present study investigated the effects of ES and TP on expression of specific regeneration-associated genes. Following a right facial nerve crush at the stylomastoid foramen, gonadectomized adult male rats were administered only ES, only TP, a combination of both, or left untreated. Real time RT-PCR analysis was used to assess fold changes in mRNA levels in the facial motor nucleus at 0 h, 6 h, 1 d, 2 d, 7 d, and 21 d post-axotomy. The candidate genes analyzed included two tubulin isoforms (alpha(1)-tubulin and beta(II)-tubulin), 43-kiloDalton growth-associated protein (GAP-43), brain derived neurotrophic factor (BDNF), pituitary adenylate cyclase-activating peptide (PACAP), and neuritin (candidate plasticity-related gene 15). The two treatments have differential effects on gene expression, with ES leading to early but transient upregulation and TP producing late but steady increases in mRNA levels. In comparison to individual treatments, the combinatorial treatment strategy has the most enhanced effects on the transcriptional program activated following injury.

Electrical stimulation facilitates rat facial nerve recovery from a crush injury

Objective To study the effect of electrical stimulation on accelerating facial nerve functional recovery from a crush injury in the rat model. Study Design Experimental. Method The main trunk of the right facial nerve was crushed just distal to the stylomastoid foramen, causing right-sided facial paralysis in 17 Sprague-Dawley rats. An electrode apparatus was implanted in all rats. Nine rats underwent electrical stimulation and eight were sham stimulated until complete facial nerve recovery. Facial nerve function was assessed daily by grading eyeblink reflex, vibrissae orientation, and vibrissae movement. Results An electrical stimulation model of the rat facial nerve following axotomy was established. The semi-eyeblink returned significantly earlier (3.71 + 0.97 vs 9.57 + 1.86 days post axotomy) in stimulated rats (P = 0.008). Stimulated rats also recovered all functions earlier, and showed less variability in recovery time. Conclusion Electrical stimulation initiates and accelerates facial nerve recovery in the rat model as it significantly reduces recovery time for the semi-eyeblink reflex, a marker of early recovery. It also hastens recovery of other functions.

Accelerating functional recovery after rat facial nerve injury: Effects of gonadal steroids and electrical stimulation

Objective We investigated the combined effects of electrical stimulation and testosterone propionate on overall recovery time in rats with extracranial crush injuries to the facial nerve. Study Design Male rats underwent castration 3 to 5 days prior to right facial nerve crush injury and electrode implantation. Rats were randomly assigned to two groups: crush injury + testosterone or crush injury with electrical stimulation + testosterone. Recovery was assessed by daily subjective examination documenting vibrissae orientation/movement, semi-eye blink, and full eye blink. Results Milestones of early recovery were noted to be significantly earlier in the groups with electrical stimulation, with/without testosterone. The addition of testosterone to electrical stimulation showed significant earlier return of late recovery parameters and complete overall recovery. Conclusion Electrical stimulation may decrease cell death or promote sprouting to accelerate early recovery. Testosterone may affect the actual rate of axonal regeneration and produce acceleration in functional recovery. By targeting different stages of neural regeneration, the synergy of electrical stimulation and testosterone appears to have promise as a neurotherapeutic strategy for facial nerve injury.

Effects of electrical stimulation and gonadal steroids on rat facial nerve regenerative properties

PURPOSE The neurotherapeutic effects of nerve electrical stimulation and gonadal steroids have independently been demonstrated. The purpose of this study was to investigate the therapeutic potential of a combinatorial treatment strategy of electrical stimulation and gonadal steroids on peripheral nerve regeneration. METHODS Following a facial nerve crush axotomy in gonadectomized adult male rats, testosterone propionate (TP), dihydrotestosterone (DHT), or estradiol (E(2)) was systemically administered with/without daily electrical stimulation of the proximal nerve stump. Facial nerve outgrowth was assessed at 4 and 7 days post-axotomy using radioactive labeling. RESULTS Administration of electrical stimulation alone reduced the estimated delay in sprout formation but failed to accelerate the overall regeneration rate. Conversely, TP treatment alone accelerated the regeneration rate by approximately 10% but had no effect on the sprouting delay. Combining TP with electrical stimulation, however, maintained the enhanced rate and reduced the sprouting delay. DHT treatment alone failed to alter the regeneration rate but combining it with electrical stimulation increased the rate by 10%. E(2) treatment alone increased the regeneration rate by approximately 5% but with electrical stimulation, there was no additional effect. CONCLUSIONS Electrical stimulation and gonadal steroids differentially enhanced regenerative properties. TP, an aromatizable androgen, augmented regeneration most, suggesting a synergism between androgenic and estrogenic effects. Therapeutically, combining electrical stimulation with gonadal steroids may boost regenerative properties more than the use of either treatment alone.

Combinatorial treatments enhance recovery following facial nerve crush.

To investigate the effects of various combinatorial treatments, consisting of a tapering dose of prednisone (P), a brief period of nerve electrical stimulation (ES), and systemic testosterone propionate (TP) on improving functional recovery following an intratemporal facial nerve crush injury.

Comparison of Extratemporal and Intratemporal Facial Nerve Injury Models

The purpose of this study was to compare functional recovery and motor nerve conduction following a distal extratemporal crush injury of the facial nerve to a more proximal intratemporal crush injury.

Facial motor nuclei cell loss with intratemporal facial nerve crush injuries in rats

Injuries of cranial nerves that are distal to but near the motor nucleus might result in retrograde motoneuron cell death. The hypothesis of this article is that an intratemporal crush injury of the facial nerve in rats can cause facial motor nuclei cell death.

10:10: Electrical Stimulation Facilitates Rat Facial Nerve Recovery

into three groups: Two groups received six hours of noise exposure (NE octave band, 105 dB SPL, centered at 4 kHz) and treated with either saline or CARBA (5.2mg/kg). One group received no noise and no treatment (controls). Treatments were given IP, one hour before and after noise and BID for two days prior to NE. Animals were humanely euthanized at two hours post-NE. Cochleae were processed for microscopy. Four IHCs from the basal turn of each ear, 16 IHCs from each group, were examined for synaptic edema using imaging software. RESULTS: Synaptic edema was found in 16 of 16 IHCs (100%) in the noise-saline, 4 of 16 (25%) in the noise-CARBA (p 0.01), and 2 of 16 in the controls (12.5%) (p 0.01). The number of dendrite edematous spaces per IHC ranged from 3-10 (average 4.13) in the noise-saline, from 1-6 (average 3) in the noise-CARBA, and from 1-4 (average 2.5) in the controls. Edema area was 34.52 21.27 (mean SD) in the noise-saline, 5.43 3.69 in the noise-CARBA (p 0.001), and 6.61 6.51 in the controls (p 0.003). CONCLUSION: The findings suggested that afferent dendrite edema from acoustic overexposure was prevented by a glutamate NMDA receptor antagonist carbamathione in a chinchilla model. SIGNIFICANCE: Using glutamate NMDA receptor antagonists for prevention of synaptic edema in acoustic overexposure will allow development of therapies to treat NIHL. SUPPORT: The Office of Naval Research and the Naval Medical Center San Diego supported this research. The views expressed are those of the authors and do not reflect the official policy or position of the Departments of the Navy, Departments of the Defense nor the United States Government.

10:00: Accelerated Rat Facial N. Recovery: Testosterone+Electrostim

into three groups: Two groups received six hours of noise exposure (NE octave band, 105 dB SPL, centered at 4 kHz) and treated with either saline or CARBA (5.2mg/kg). One group received no noise and no treatment (controls). Treatments were given IP, one hour before and after noise and BID for two days prior to NE. Animals were humanely euthanized at two hours post-NE. Cochleae were processed for microscopy. Four IHCs from the basal turn of each ear, 16 IHCs from each group, were examined for synaptic edema using imaging software. RESULTS: Synaptic edema was found in 16 of 16 IHCs (100%) in the noise-saline, 4 of 16 (25%) in the noise-CARBA (p 0.01), and 2 of 16 in the controls (12.5%) (p 0.01). The number of dendrite edematous spaces per IHC ranged from 3-10 (average 4.13) in the noise-saline, from 1-6 (average 3) in the noise-CARBA, and from 1-4 (average 2.5) in the controls. Edema area was 34.52 21.27 (mean SD) in the noise-saline, 5.43 3.69 in the noise-CARBA (p 0.001), and 6.61 6.51 in the controls (p 0.003). CONCLUSION: The findings suggested that afferent dendrite edema from acoustic overexposure was prevented by a glutamate NMDA receptor antagonist carbamathione in a chinchilla model. SIGNIFICANCE: Using glutamate NMDA receptor antagonists for prevention of synaptic edema in acoustic overexposure will allow development of therapies to treat NIHL. SUPPORT: The Office of Naval Research and the Naval Medical Center San Diego supported this research. The views expressed are those of the authors and do not reflect the official policy or position of the Departments of the Navy, Departments of the Defense nor the United States Government.