Intranasal Administration Of Nerve Growth Factor Research Articles

Topical delivery of nerve growth factor for treatment of ocular and brain disorders

Neurotrophins are a family of proteins that support neuronal proliferation, survival, and differentiation in the central and peripheral nervous systems, and are regulators of neuronal plasticity. Nerve growth factor is one of the best-described neurotrophins and has advanced to clinical trials for treatment of ocular and brain diseases due to its trophic and regenerative properties. Prior trials over the past few decades have produced conflicting results, which have principally been ascribed to adverse effects of systemic nerve growth factor administration, together with poor penetrance of the blood-brain barrier that impairs drug delivery. Contrastingly, recent studies have revealed that topical ocular and intranasal nerve growth factor administration are safe and effective, suggesting that topical nerve growth factor delivery is a potential alternative to both systemic and invasive intracerebral delivery. The therapeutic effects of local nerve growth factor delivery have been extensively investigated for different ophthalmic diseases, including neurotrophic keratitis, glaucoma, retinitis pigmentosa, and dry eye disease. Further, promising pharmacologic effects were reported in an optic glioma model, which indicated that topically administered nerve growth factor diffused far beyond where it was topically applied. These findings support the therapeutic potential of delivering topical nerve growth factor preparations intranasally for acquired and degenerative brain disorders. Preliminary clinical findings in both traumatic and non-traumatic acquired brain injuries are encouraging, especially in pediatric patients, and clinical trials are ongoing. The present review will focus on the therapeutic effects of both ocular and intranasal nerve growth factor delivery for diseases of the brain and eye.

Intranasal nerve growth factor administration improves neurological outcome after GBS meningitis.

Nerve growth factor (NGF) is a neurotrophin that promotes neural recovery and plasticity after experimental brain injury, supporting neuronal growth, differentiation, and survival of brain cells. Only a few studies reported NGF administration in pediatric patients with impaired brain functions after traumatic injuries, ischemic or infectious diseases, such as meningitis. We described the beneficial therapeutic effects of human-recombinant nerve growth factor (hr-NGF) treatment in an infant with persistent unresponsive wakefulness syndrome (UWS), due to late-onset group B Streptococcus meningitis. The infant received five monthly cycles of intranasal hr-NGF (0.1mg/kg, 3 times daily for 7 consecutive days) through a mucosal atomizer device (MAD). NGF administration improved functional [positron emission tomography/computed tomography (PET/CT), single-photon emission/computed tomography (SPECT/CT), and magnetic resonance imaging (MRI)] assessments, electrophysiological [Electroencephalogram (EEG)] studies, as well as main cognitive processes and clinical and neurological functions. After hr-NGF treatment, significant improvements in facial mimicry, attention, motor reactions, oral motility, and feeding capacity were observed. She also recovered some hypothalamic functions and her cough reflex was restored. No side effects were reported during and after the treatment. For the first time ever, hr-NGF has been successfully utilized in an infant with UWS and severe neurologic outcome due to a bacterial meningitis. Although further studies are needed for better understanding the neuroprotective role of this neurotrophin, intranasal hr-NGF administration appears to be a promising and save rescuing strategy treatment in infants with severe neurological impairment after brain damage.

Intranasal nerve growth factor bypasses the blood-brain barrier and affects spinal cord neurons in spinal cord injury.

The purpose of this work was to investigate whether, by intranasal administration, the nerve growth factor bypasses the blood-brain barrier and turns over the spinal cord neurons and if such therapeutic approach could be of value in the treatment of spinal cord injury. Adult Sprague-Dawley rats with intact and injured spinal cord received daily intranasal nerve growth factor administration in both nostrils for 1 day or for 3 consecutive weeks. We found an increased content of nerve growth factor and enhanced expression of nerve growth factor receptor in the spinal cord 24 hours after a single intranasal administration of nerve growth factor in healthy rats, while daily treatment for 3 weeks in a model of spinal cord injury improved the deficits in locomotor behaviour and increased spinal content of both nerve growth factor and nerve growth factor receptors. These outcomes suggest that the intranasal nerve growth factor bypasses blood-brain barrier and affects spinal cord neurons in spinal cord injury. They also suggest exploiting the possible therapeutic role of intranasally delivered nerve growth factor for the neuroprotection of damaged spinal nerve cells.

Intranasal delivery of nerve growth factor attenuates aquaporins-4-induced edema following traumatic brain injury in rats

Traumatic brain injury (TBI) remains the leading cause of injury-related death and disability. Brain edema, one of the most major complications of TBI, contributes to elevated intracranial pressure, and poor prognosis following TBI. Nerve growth factor (NGF) appears to be a viable strategy to treat brain edema and TBI. Unfortunately, due to its poor blood-brain barrier (BBB) permeability, the clinical application of NGF has been greatly limited. We previously demonstrated that intranasal NGF could bypass the BBB and distribute throughout the brain. Here we further studied whether intranasal NGF could attenuate TBI-induced brain edema and its putative mechanisms. TBI was produced by a modified weight-drop model. We found that intranasal administration of NGF (5μg/d) attenuated the brain edema, as assayed by hemisphere water content, at 12h, 24h and 72h after TBI induction. This attenuation was associated with a prominent decrease of the content of aquaporin-4, which plays a pivotal role in the formation of brain edema. By the use of RT-PCR and ELISA, we showed that intranasal NGF markedly inhibited the transcription and expression of pro-inflammatory cytokines including IL-1β and TNF-α. An electrophoretic mobility shift assay (EMSA) displayed a significant activation of nuclear factor-κB following TBI, which was, however, much lowered in the NGF-treated rats. Furthermore, upon intranasal NGF supplementation, mitochondria-mediated apoptosis following TBI was minimized, as indicated by upregulation of Bcl-2 and downregulation of caspase-3. Collectively, our findings suggested that intranasal NGF may be a promising strategy to treat brain edema and TBI.

Combination therapy with intranasal NGF and electroacupuncture enhanced cell proliferation and survival in rats after stroke

Objective: This work was designed to investigate the effects of the combination therapy with intranasal (IN) administration of nerve growth factor (NGF) and electroacupuncture (EA) on neural progenitors and neurological functional recovery in adult rats after focal ischemia.Methods: Rats subjected to 2 hours of middle cerebral artery occlusion (MCAO) were randomly assigned to four groups: Group 1, IN administration of phosphate-buffered saline (PBS) for control; Group 2, IN administration of NGF alone; Group 3, EA with IN administration of PBS; Group 4, IN administration of NGF with EA. Treatments were initiated at 2 hours after MCAO and continued for three consecutive days. All animals received daily injections of 5-bromodeoxyuridine (BrdU) intraperitoneally for 7 days starting at 24 hours after reperfusion and were killed at 2 hours or 21 days after the last BrdU injection. Neurological function and infarct volume were evaluated. Immunohistochemistry for BrdU was performed to identify newborn cells in the ipsilateral subventricular zone and striatum.Results: The combination treatment led to significant improvement in neurological function and reduction in infarct volume. Cell proliferation and survival of progenitors were enhanced in rats treated with the combination treatment.Conclusion: These results suggest that IN administration of NGF and EA may have a synergistic effect in preventing ischemic injury and enhancing functional recovery after focal cerebral ischemia, which may be attributed to enhanced cell proliferation and survival.

Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice

Nerve growth factor (NGF) delivery to the brain of patients appears to be an emerging potential therapeutic approach to neurodegenerative disease, such as Alzheimer's disease (AD). The intranasal route of administration could provide an alternative to intracere-broventricular infusion and gene therapy. We previously showed that intranasal administration of NGF determined an amelioration of cholinergic deficit and a decrease in the number of phosphotau-positive neurons and of beta-amyloid accumulation in AD11 mice, which express transgenic antibodies neutralizing NGF action and exhibit a progressive Alzheimer-like neurodegeneration. In this study, we report that the Alzheimer-like neurodegeneration in AD11 mice is linked to progressive behavioral deficits in visual recognition memory and spatial memory starting from 4 months of age. To establish whether intranasal administration of NGF, started after the appearance of the first memory deficits, could revert the cognitive deficits in AD11 mice, we assessed the performance of NGF-treated or control AD11 mice in the object recognition test and in a test of memory for place and context. Deficits exhibited by untreated AD11 mice could be rescued by the intranasal administration of NGF. Thus, this route of administration provides a promising way to deliver NGF to the brain in a therapeutic perspective.