Subcutaneous tri‐block copolymer produces recovery from spinal cord injury

Abstract

We have studied the ability of nonionic detergents and hydrophilic polymers to seal permeabilized membranes of damaged cells, rescuing them from progressive dissolution, degeneration, and death. We report that a single subcutaneous injection of the tri-block copolymer, Poloxamer 188 (P188) 6 hr after a severe compression of the adult guinea pig spinal cord is able to: (1). preserve the anatomic integrity of the cord; (2). produce a rapid recovery of nerve impulse conduction through the lesion; and (3). produce a behavioral recovery of a spinal cord dependent long tract spinal cord reflex. These observations stood out against a control group in blinded evaluation. Conduction through the lesion was monitored by stimulating the tibial nerve of the hind limb, and measuring the arrival of evoked potentials at the contralateral sensory cortex of the brain (somatosensory evoked potentials; SSEP). Behavioral recovery was determined by a return of sensitivity of formerly areflexic receptive fields of the cutaneous trunchi muscle (CTM) reflex. This contraction of back skin in response to tactile stimulation is totally dependent on the integrity of an identified bilateral column of ascending long tract axons. A statistically significant recovery of both SSEP conduction through the lesion and the CTM reflex occurred in P188-treated animals compared to vehicle-treated controls. Quantitative 3D computer reconstruction of the lesioned vertebral segment of spinal cord revealed a statistically significant sparing of spinal cord parenchyma and a significant reduction in cavitation of the spinal cord compared to control animals We determined that the proportion of P188-treated animals that recovered evoked potentials were nearly identical to that produced by a subcutaneous injection of polyethylene glycol (PEG). In contrast, P188 was not as effective as PEG in producing a recovery of CTM functioning. We discuss the likely differences in the mechanisms of action of these two polymers, and the possibilities inherent in a combined treatment.

The Effect of Poloxamer-188 on Neuronal Cell Recovery from Mechanical Injury

“…Although our data and that from other cell culture models (Geddes et al, 2003) suggest a relatively transient change in permeability with membranes resealing spontaneously in less than 1 h, other studies suggest a somewhat longer period of membrane disruption (2-4 h; Ellis et al, 1995). Recently, the study conducted by Borgens et al (2004) in adult guinea pig spinal cord injured with compression showed that subcutaneous injection of P188 after 6 h post-injury provided a significant recovery of spinal cord function. Based on our LDH release data, we considered a 15-min interval after the injury to be a good test for its ability to rescue injured neurons in this model.…”

“…In a spinal cord compression injury model, P188 administered subcutaneously promoted restoration of cord function (Borgens et al, 2004). As with all therapeutic agents targeted to the brain, adequate delivery to the site of injury will have to be achieved including crossing of the blood brain barrier if injected intravenously.…”

“…3). Exposing electroporated cells to this surfactant effectively seals the damaged membranes; thereby, acutely arresting the leakage of intracellular components in vivo and in vitro (Hanning et al, 2000;Lee et al, 1992Lee et al, , 1994Merchant et al, 1998;Terry et al, 1999;Borgens et al, 2004). Recently, Marks et al (2001) reported that P188 is effective in restoring the integrity of injured membranes of electroporated neuronal cells.…”

Three-dimensional imaging of living and dying neurons with atomic force microscopy

“…The mechanisms of action underlying polymer-mediated rescue and repair is far from clear (Borgens, 2001(Borgens, , 2003. The AFM will allow us to probe the behavior of polymers like polyethylene glycol (Borgens et al, 2002) and Poloxamer 188 (Borgens et al, 2004) with damaged nerve membranes by directly observing the molecules interaction with the membrane rupture while quantitatively monitoring relevant characteristics such as changes in membrane pressure in contact mode during the repair process. In short, the application of AFM to studies of neurobiology has "barely scratched the surface".…”

The limitation of acute necrosis in retro-patellar cartilage after a severe blunt impact to the in vivo rabbit patello-femoral joint

“…Due to the nature of necrosis, mild surfactants have been used to restore integrity to cells after physical and chemical stresses [4,24]. Specifically, poloxamer 188 (P188) was found to 'save' neurons from early necrosis after severe mechanical loading [2,18]. We recently found that P188 surfactant was able to 'save' chondrocytes from acute necrosis in bovine chondral explants subjected to 25MPa of unconfined compression [25].…”