Search

Background: Nerve growth factor (NGF) promotes neural recovery after experimental traumatic brain injury (TBI) supporting neuronal growth, differentiation and survival of brain cells and up-regulating the neurogenesis-associated protein Doublecortin (DCX). Only a few studies reported NGF administration in paediatric patients with severe TBI., Methods: A four-year-old boy in a persistent unresponsive wakefulness syndrome (UWS) was treated with intranasal murine NGF administration 6 months after severe TBI. The patient received four cycles of intranasal NGF (0.1 mg/kg, twice a day for 10 consecutive days)., Results: NGF administration improved functional [Positron Emission Tomography/Computed Tomography (PET/CT); Single photon emission/Computed Tomography (SPECT/CT) and Magnetic Resonance Imaging (MRI)] assessment, electrophysiological [Electroencephalogram (EEG) and Visual Evoked Potential (VEP)] studies and clinical conditions. He showed improvements in voluntary movements, facial mimicry, phonation, attention and verbal comprehension, ability to cry, cough reflex, oral motility, feeding capacity, and bowel and urinary functions. After NGF administration, raised levels of both NGF and DCX were found in the cerebrospinal fluid of the patient. No side effects were reported., Conclusions: Although further studies are needed for better understanding the neuroprotective role of this neurotrophin, intranasal NGF administration appears to be a promising and safe rescuing strategy treatment in children with neurological impairment after TBI.

Background: In the adult brain, migrating neuroblasts can replace damaged neurons after severe traumatic brain injury (TBI). Little is known about which factors determine the magnitude and amplification of neurogenesis after TBI, but there are some evidences that the nerve growth factor (NGF) and the doublecortin (DCX) can influence neurogenesis and neuronal repair., Methods: This study investigates the NGF and DCX levels in the cerebrospinal fluid of 12 children with severe TBI and 12 matched controls, to determine the correlation between the expression of both these factors and the patients outcome. We collected cerebrospinal fluid samples 2 hours (Time T1) and 48 hours (Time T2) after brain injury. NGF levels were measured using a two-site immunoenzymatic assay, whereas the DCX expression by a Western blot analysis., Results: At time T1 and T2, children with the best outcomes had higher levels of NGF than children with poor outcomes. Evaluating the change of NGF levels from time T1 to time T2, we found that the NGF up-regulation in the early time after injury was significantly associated with good outcomes of patients. Concomitantly, the expression of DCX increased only in patients with NGF up-regulation from time T1 to time T2. In others patients and in controls the expression of DCX remained unchanged., Conclusion: Based on these results, we hypothesize that NGF and DCX contribute to the mechanisms of neuroprotection and neuronal connection reorganization after TBI, playing a key role in the outcome of these patients.

Background: Secondary brain damage after traumatic brain injury (TBI) involves neuro-inflammatory mechanisms, mainly dependent on the intracerebral production of cytokines. In particular, interleukin 1beta (IL-1beta) is associated with neuronal damage, while interleukin 6 (IL-6) exerts a neuroprotective role due to its ability to modulate neurotrophins biosynthesis. However, the relationship between these cytokines and neurotrophins with the severity and outcome of TBI remains still controversial., Aims: To determine whether the concentration of IL-1beta and IL-6 and neurotrophins (nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF)) in the cerebrospinal fluid (CSF) of children with TBI correlates with the severity of the injury and its neurologic outcome., Methods: Prospective observational clinical study in a university hospital. CSF samples were collected from 27 children at 2h (Time T1) and 48 h (Time T2) after severe TBI, and from 21 matched controls. Severity of TBI was evaluated by GCS and neurologic outcome by GOS. CSF concentrations of cytokines and neurotrophins were measured by immunoenzymatic assays., Results: Early NGF and IL-1beta concentrations (T1) correlated significantly with the severity of head injury, whereas no correlation was found for IL-6, BDNF, and GDNF. Furthermore, higher NGF and IL-6 and lower IL-1beta expression at T2 were associated with better neurologic outcomes. No significant association was found between BDNF or GDNF expression and neurologic outcome., Conclusions: NGF concentration in CSF is a useful marker of brain damage following severe TBI and its up-regulation, in the first 48 h after head injury together with lower IL-1beta expression, correlates with a favorable neurologic outcome. Clinical and prognostic information may also be obtained from IL-6 expression.

Objective and Importance: Hypoxic-ischemic brain injuries in childhood are associated with poor neurological outcome. Recently, experimental and clinical works show that nerve growth factor (NGF) reduces neurological deficits and promotes endothelial cells proliferation and angiogenesis following hypoxic-ischemic brain injuries. After brain stroke, new neurons express a protein, called doublecortin (DCX), which indicates a new marker for neurogenesis and migrating neuroblasts. This study investigates the effects of intraventricular NGF administration in two infants with severe hypoxic-ischemic brain damage and its role in both the cerebral perfusion and neurogenesis., Clinical Presentation: Two infants, aged 8 and 13 months, with hypoxic-ischemic brain damage, secondary to prolonged cardiorespiratory arrest, were treated with intraventricular NGF administration. Before the therapy, both infants were comatose, aphasic and showed flaccid tetraparesis. After 1 month NGF treatment, their neurological conditions improved, electro-encephalography (EEG) examinations showed increased alpha/theta ratio, and single photon emission computed tomography (SPECT) works demonstrated a better cerebral perfusion. The DCX expression in the cerebrospinal fluid (CSF) increased concomitantly with increasing levels of NGF., Intervention: The drug utilized was 2.5S NGF purified and lyophilized from male mouse submaxillary glands. The NGF administration was started 4 months after ischemic brain injury. NGF (0.1 mg) was administered via the external drainage catheter into the right cerebral ventricle once a day for 10 consecutive days., Conclusion: Our study shows that the intraventricular NGF administration improves the cerebral perfusion and stimulates the pathway of neurogenesis differentiation with the activation of DCX biosynthesis.

Secondary brain damage after traumatic brain injury (TBI) involves neuro-inflammatory mechanisms that are mainly dependent on the intracerebral production of cytokines. Interleukin-6 (IL-6) may have a role both in the pathogenesis of neuronal damage and in the recovery mechanisms of injured neurons through the modulation of nerve growth factor (NGF) biosynthesis. However, the relationship between IL-6 and NGF expression and the severity and outcome of TBI remains controversial. We have conducted a prospective observational clinical study to determine whether the concentration of IL-6 and NGF in the cerebrospinal fluid (CSF) of children with TBI correlates with the severity of the injury and neurologic outcome of patients. CSF samples were collected from 29 children at 2 h (time T1) and 48 h (time T2) after severe TBI, and from 31 matched controls. TBI severity was evaluated by Glasgow Coma Scale (GCS) and neurologic outcome by Glasgow Outcome Score (GOS). CSF concentrations of IL-6 and NGF were measured by immunoenzymatic assays. Early NGF concentrations (T1) correlated significantly with head injury severity, whereas no correlation was found between GCS and IL-6. Furthermore, IL-6 and NGF upregulation after injury was associated with better neurologic outcomes. Based on these findings, we posit that NGF expression is a useful marker of brain damage following severe TBI. Moreover, the early upregulation of both IL-6 and NGF, which correlates with a favorable neurologic outcome, may reflect an endogenous attempt at neuroprotection in response to the damaging biochemical and molecular cascades triggered by traumatic insult.

Objective and Importance: Hypoxic-ischemic brain injuries in childhood are associated with poor neurological outcome. Unfortunately, no new therapeutic approaches have been proposed. Recently, animal studies show that nerve growth factor (NGF) can reduce neurological deficits following hypoxic-ischemic brain injuries. The objective of this study is to demonstrate the therapeutic effects of intraventricular NGF infusion in severe post-ischemic damage., Clinical Presentation: Two infants, aged 9 and 8 months, with hypoxic-ischemic brain damage, secondary to prolonged cardiorespiratory arrest and stabilized after the conventional treatment, were treated with intraventricular NGF infusion. Before the therapy both infants were comatose with asymmetrical tetraparesis; their Glasgow Coma Scale (GCS) was 4 and 5, respectively. One month after the treatment, their GCS was 8 and 9, respectively. EEG examinations performed after the NGF infusion showed an increased alpha/theta ratio. MRI showed a reduction of malacic areas in the brain. A SPECT study, performed only in one infant, demonstrated that the NGF treatment resulted in an improvement of regional cerebral perfusion in right temporal and occipital cortices., Intervention: The drug utilized was 2.5S NGF purified and lyophilized from male mouse submaxillary glands. NGF infusion was started about 30 days after the hypoxic-ischemic brain injury. 0.1 mg NGF was administered via the external drainage catheter into the right cerebral ventricle once a day for 10 days consecutively., Conclusion: Our observations are interesting, but further studies are necessary to confirm the effects of NGF in hypoxic-ischemic brain injuries in infants.

The cause of motor neuron death in spinal muscular atrophy is still debated. In experimental animal models, neurotrophic factors have great potency in supporting motor neuron survival and differentiation, but there are no clinical studies on neurotrophin involvement in disease progression and motor neuron dysfunction. The aim of this study was to investigate the expression of three neurotrophic factors: nerve growth factor, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor in the cerebrospinal fluid of six infants with spinal muscular atrophy type I and six controls. The levels of neurotrophic factors were measured using an immunoenzymatic assay. A statistically significant increase in glial cell-derived neurotrophic factor levels was observed in patients with spinal muscular atrophy, compared with controls, whereas nerve growth factor and brain-derived neurotrophic factor did not show significant differences between groups. Glial cell-derived neurotrophic factor is one of the most powerful survival factors for spinal motor neurons. The increase of glial cell-derived neurotrophic factor may represent a response to the loss and damage of neuronal cells at the site of spinal lesion and is possibly related to axonal sprouting and synaptic reorganization of the damaged spinal motor neurons. [Copyright &y& Elsevier]