Recombinant human TNFα induces concentration-dependent and reversible alterations in the electrophysiological properties of axons in mammalian spinal cord

Increased expression of the proinflammatory cytokine tumor necrosis factor-alpha (TNF alpha) and its soluble receptors is evident within the central nervous system (CNS) following traumatic brain injury and spinal cord injury. TNFa is integral to the acute inflammatory cascade that follows neurotrauma and has been shown to have both beneficial and detrimental properties. We examined the effects of varying concentrations (1-5000 ng/mL) of recombinant human TNFa (rhTNF alpha) on select electrophysiological properties of excised guinea pig spinal cord tissue. Pulsed electrical stimuli (0.33 Hz) were delivered to strips of isolated ventral white matter in a double sucrose gap chamber. Recordings were made of the compound action potential (CAP) and membrane potential before, during, and after bathing the tissue with rhTNFa for 30 min. Increasing concentrations of rhTNFa yielded progressively greater reductions in amplitude of the CAP that were temporally associated with depolarization of the resting compound membrane potential. These effects were largely reversed on washout of rhTNFa and were not present when heat-denatured rhTNFa was introduced. The results provide evidence that elevated concentrations of TNFa induce reversible depolarization of the compound membrane potential and reduction in CAP amplitude, sometimes to the point of extinction of the CAP, suggestive of impaired axonal conduction. These observations point to a new mechanism of immune-mediated central conduction deficit. Cytokine-induced alterations in membrane properties and axonal conduction may contribute to neurological deficits following CNS injury by compounding trauma-induced myelinopathy and axonopathy.