Endogenous NGF and CNTF levels in human peripheral nerve injury.

Nerve growth factor (NGF) is trophic to sensory and sympathetic fibres, and ciliary neurotrophic factor (CNTF) to motoneurones, in animal models of peripheral nerve injury: NGF excess produces hyperalgesia. In this first study of injured human nerves and sensory ganglia, we quantified and localized endogenous NGF and CNTF in 59 neonate and adult patients with brachial plexus and peripheral nerve injury. NGF levels were generally depleted in injured nerves, but relatively preserved acutely in nerve segments distal to injury. NGF immunostaining was observed in Schwann cells in distal nerve segments with pockets of high levels in some neuromas. CNTF levels and immunostaining in Schwann cells were markedly decreased distally within days of injury. We propose that early local administration of NGF and CNTF-like agents may help prevent degenerative changes in injured nerves, while at later stages local anti-NGF treatment (e.g. of some neuromas) may ameliorate chronic pain.

Increased nerve growth factor levels in the urinary bladder of women with idiopathic sensory urgency and interstitial cystitis.

OBJECTIVES: To determine whether nerve growth factor (NGF) is elevated in painful conditions of the urinary bladder (idiopathic sensory urgency, interstitial cystitis and painful chronic cystitis). PATIENTS AND METHODS: Sixteen women patients were recruited from the Urodynamic Clinic at The Elizabeth Garrett Anderson Hospital, London. Four each had idiopathic sensory urgency (mean age 34 years, range 24-51), chronic cystitis (mean age 51 years, range 40-79) and interstitial cystitis (mean age 41 years, range 29-53). Four women who had genuine stress incontinence on cystometry but with no irritative symptoms were used as controls (mean age 45 years, range 35-54). The levels of NGF were determined in bladder biopsies from all women and biopsy sections were immunostained to detect NGF. RESULTS: The levels of NGF were higher in samples from all three painful bladder conditions than in samples from controls. Immunostaining showed increased NGF expression in the urothelium, most marked in patients with idiopathic sensory urgency. CONCLUSIONS: The increased level of NGF may explain several clinical and pathological features in these conditions, including sensitization of nociceptor fibres and increased numbers of mast cells. We propose that anti-NGF treatment may be a rational and effective treatment in intractable bladder pain.

The role of endogenous nerve growth factor in human diabetic neuropathy.

Nerve growth factor (NGF) is trophic to sensory and sympathetic fibers. In animal models, NGF is depleted in diabetic nerves and NGF deprivation produces hypoalgesia. Exogenous NGF can reverse some of the pathological changes in diabetic nerves and NGF excess leads to hyperalgesia. We have quantified sensory and autonomic function in early diabetic polyneuropathy and correlated changes with levels of NGF and neuropeptides in affected skin. We describe an early length-dependent dysfunction of sensory small-diameter fibers, prior to dysfunction of sympathetic fibers, with depletion of skin NGF and the sensory neuropeptide substance P. We describe a significant correlation between NGF depletion and decreased skin axon-reflex vasodilation, mediated by small sensory fibers partly via substance P release. Immunostaining shows depletion of NGF in keratinocytes in diabetic skin. We propose that a decrease in endogenous skin-derived NGF influences the presentation of diabetic polyneuropathy, although metabolic or vascular abnormalities may be the cause of the neuropathy. As loss of nociception and axon-reflex vasodilation contribute to diabetic foot ulceration, early and prolonged NGF treatment at an appropriate dose may provide rational prophylaxis for this condition.

Regional changes of ciliary neurotrophic factor and nerve growth factor levels in post mortem spinal cord and cerebral cortex from patients with motor disease.

Ciliary neurotrophic factor (CNTF) rescues motor neurons in animal models of injury and neurodegeneration, and disruption of the mouse CNTF gene results in motor neuron degeneration in mature adults. Glial cells increase nerve growth factor (NGF) expression in neuropathological conditions, and the sensory system can be affected in the amyotrophic lateral sclerosis (ALS) type of motor neuronic disease. We therefore studied CNTF and NGF levels in post mortem spinal cord and cerebral cortex from patients with ALS and matched controls. We report a marked decrease of CNTF in the ventral horn of spinal cord in ALS, with no change in cerebral motor cortex. In contrast, NGF levels were decreased in ALS cerebral motor cortex, where the corticospinal tract originates, but increased in the lateral column of spinal cord, which includes the region of corticospinal tract degeneration in ALS. Both CNTF and NGF levels were decreased in ALS dorsal spinal cord.

Nerve growth factor levels in cultured human skin cells: effect of gestation and viral transformation.

Extracts of cultured human keratinocytes and fibroblasts were assayed for nerve growth factor-like immunoreactivity (NGF) by a specific enzyme-linked immunoabsorbant assay. NGF levels were higher in primary cultured keratinocytes than in freshly isolated keratinocytes or culture through multiple passages. Viral transformation of keratinocytes with the human papilloma virus (HPV16) significantly increased NGF levels, whilst transformation with the simian virus (SV40), which induces simple epithelial differentiation, reduced the concentration of NGF. Passaged epidermal keratinocytes contained more than twice as much NGF as did passaged fibroblasts. Oral keratinocytes and fibroblasts, and psoriatic fibroblasts, all from high turnover tissues, did not contain significantly different levels of NGF in culture than dermal keratinocytes or fibroblasts. Foetal fibroblasts contained five times as much NGF as did adult fibroblasts. These results suggest that basal keratinocytes are a major but not sole source of NGF in human skin, and that NGF may play a role in human skin development.