Neurotrophin-3 Prevents the Proximal Accumulation of Neurofilament Proteins in Sensory Neurons of Streptozocin-Induced Diabetic Rats

Abstract

The relation between neurofilament expression and/or phosphorylation in the proximal versus distal components of the sensory peripheral neuraxis was studied and related to disorders in structure and function of the distal axon of streptozocin (STZ)-induced diabetic rats studied for 14 weeks. The ability of neurotrophin-3 (NT-3) to prevent abnormalities in neurofilament biology was also investigated. Compared with age-matched controls, neurofilament heavy (NF-H) (3.3-fold) and neurofilament medium (NF-M) (2.5-fold), but not neurofilament light (NF-L), subunits accumulated in the proximal axon of sensory neurons of the lumbar dorsal root ganglia (DRG) in untreated diabetic rats. Neurofilament accumulation was prevented by NT-3. Smalland large-diameter sensory neurons exhibited elevated levels of NF-H protein accumulation and phosphorylation in the DRG of untreated diabetic rats, levels that were ameliorated by NT-3. The sural nerve of untreated diabetic rats showed a 50% decrease in the levels of NF-H and NF-M, but not NF-L, subunits; NT-3 only partially normalized the defect in NF-M expression. These observations were associated with significant lowering of motor and sensory nerve conduction velocity but no alteration in the mean axonal diameter of myelinated axons in the sural nerve in untreated diabetic rats. It is proposed that the accumulation of NF-H and NF-M subunits in the proximal axon is an etiologic factor in the distal axon degeneration observed in diabetes. [NF-L]). In the streptozocin (STZ) and BB rodent models of type 1 diabetes, structural abnormalities in peripheral nerve include decreased axonal caliber or axonal dwindling (1-3). Studies in type 1 diabetic rats show reduced expression of neurofilaments in sensory neurons (1,4,5), reduced axonal transport of neurofilament in sensory axons (6), loss of neurofilament in distal nerve (1-3,7), and abnormal neurofilament phosphorylation in the dorsal root ganglia (DRG), spinal cord, and sciatic nerve (8 -11). Aberrant phosphorylation of NF-H and NF-M subunits in DRG of STZ-and BB-diabetic rats is associated with activation of c-jun NH 2 -terminal kinase (JNK) (10). The stress-activated protein kinases (SAPKs: extracellular signal-regulated kinase [ERK], JNK, and p38) are well-characterized proteins that phosphorylate neurofilaments and are activated by hyperglycemia and oxidative stress in cultured sensory neurons (11-13).Nerve crushϪinduced loss of neurofilament expression in the small-to-medium subpopulation of neurons in the DRG is ameliorated by nerve growth factor treatment (14,15). Sequestration of the high-affinity receptor for neurotrophin-3 (NT-3) results in motor and sensory nerve conduction velocity (NCV) deficits similar to those that develop after nerve transection (16). Exogenous NT-3 provided after physical nerve injury can prevent and reverse a range of injury-evoked responses (16 -18) and also enhance subsequent regeneration (19). Systemic NT-3 treatment has also been shown to prevent toxin-induced peripheral neuropathies (20,21). Dem...

Uncoupling Proteins Prevent Glucose-Induced Neuronal Oxidative Stress and Programmed Cell Death

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Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice

“…Complications associated with neurofilament phosphorylation were avoided in this study by choosing an NF-H antibody that is not sensitive to neurofilament phosphorylation. Importantly, NT-3 treatment reduces these deficits, consistent with our findings regarding NT-3 treatment (Mizisin et al, 1999;Fernyhough et al, 1999;Sayers et al, 2003). Interestingly, we also demonstrate that mice treated with NT-3 displayed a significant increase in Merkel cells associated with nerve fibers, suggesting that NT-3 treatment stimulated formation and innervation of sensory receptors de novo.…”

Oxidative injury and neuropathy in diabetes and impaired glucose tolerance

“…Even though there is evidence of a small DRG neuronal loss, the number of DRG neurons showing evidence of oxidative injury is greater than the measured loss of neurons. This may occur because activation of caspases does not invariably result in neuronal death, or because of an intrinsic capacity for repair within the neuron (Sayers et al, 2003). However, overall the pathology points to a chronic dysfunction of neurons under diabetic conditions.…”