Traumatic brain injury is one of the main causes of mortality and disability worldwide.Traumatic brain injury is characterized by a primary injury directly induced by the impact,which progresses into a secondary injur...Traumatic brain injury is one of the main causes of mortality and disability worldwide.Traumatic brain injury is characterized by a primary injury directly induced by the impact,which progresses into a secondary injury that leads to cellular and metabolic damages,starting in the first few hours and days after primary mechanical injury.To date,traumatic brain injury is not targetable by therapies aimed at preventing and/or limiting the outcomes of secondary damage but only by palliative therapies.Nerve growth factor is a neurotrophin targeting neuronal and non-neuronal cells,potentially useful in preventing/limiting the outcomes of secondary damage in traumatic brain injury.This potential has further increased in the last two decades since the possibility of reaching neurotrophin targets in the brain through its intranasal delivery has been exploited.Indeed,molecules intranasally delivered to the brain parenchyma may easily bypass the blood-brain barrier and reach their therapeutic targets in the brain,with favorable kinetics,dynamics,and safety profile.In the first part of this review,we aimed to report the traumatic brain injury-induced dysfunctional mechanisms that may benefit from nerve growth factor treatment.In the second part,we then exposed the experimental evidence relating to the action of nerve growth factor(both in vitro and in vivo,after administration routes other than intranasal)on some of these mechanisms.In the last part of the work,we,therefore,discussed the few manuscripts that analyze the effects of treatment with nerve growth factor,intranasally delivered to the brain parenchyma,on the outcomes of traumatic brain injury.展开更多
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 b...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.展开更多
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 i...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.展开更多
基金funded by the Italian Ministry of Health Grant:RF-2018-12366594“Nerve growth factor in paediatric severe traumatic brain injury:translational and clinical studies on a candidate biomarker and therapeutic drug”(to AC)。
文摘Traumatic brain injury is one of the main causes of mortality and disability worldwide.Traumatic brain injury is characterized by a primary injury directly induced by the impact,which progresses into a secondary injury that leads to cellular and metabolic damages,starting in the first few hours and days after primary mechanical injury.To date,traumatic brain injury is not targetable by therapies aimed at preventing and/or limiting the outcomes of secondary damage but only by palliative therapies.Nerve growth factor is a neurotrophin targeting neuronal and non-neuronal cells,potentially useful in preventing/limiting the outcomes of secondary damage in traumatic brain injury.This potential has further increased in the last two decades since the possibility of reaching neurotrophin targets in the brain through its intranasal delivery has been exploited.Indeed,molecules intranasally delivered to the brain parenchyma may easily bypass the blood-brain barrier and reach their therapeutic targets in the brain,with favorable kinetics,dynamics,and safety profile.In the first part of this review,we aimed to report the traumatic brain injury-induced dysfunctional mechanisms that may benefit from nerve growth factor treatment.In the second part,we then exposed the experimental evidence relating to the action of nerve growth factor(both in vitro and in vivo,after administration routes other than intranasal)on some of these mechanisms.In the last part of the work,we,therefore,discussed the few manuscripts that analyze the effects of treatment with nerve growth factor,intranasally delivered to the brain parenchyma,on the outcomes of traumatic brain injury.
基金supported by Proj.PRIN prot.2007AF3XH4_005,"Fondazione Cassa di Risparmio di Roma",and"Ministero della Salute"Grant No.RF-FGB-2005-150198
文摘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.
文摘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.
