Restorative Neurology and Neuroscience

Purpose: Testosterone (T) treatment accelerates recovery from facial paralysis after facial nerve crush in hamsters. In this study, we extended those studies to another injury model and asked the following question: Will T treatment accelerate recovery from lower limb paralysis following sciatic nerve crush in the rat? Methods: Castrated adult male rats received a right side sciatic nerve crush at the level of the sciatic notch, with the left side serving as control. Half the animals received a subcutaneous implant of a propionated form of T (TP), the others were sham-implanted. Weekly testing using the Sciatic Functional Index (SFI), a quantitative measure of locomotion, was done for 7 weeks postoperative (wpo). Results: Between 3 and 5 weeks post-op, the average SFI score of the TP-treated group was higher than controls. This difference was significant at 4 wpo, indicating an accelerated degree of functional recovery. At these timepoints, the differences were attributable to the footprint or paw length and associated with calf muscle reinnervation rather than the toespreading component associated with intrinsic foot muscle rein-nervation. Beyond 5 wpo, there were no differences in the SFI scores. Conclusion: The results indicate that, as with facial nerve regeneration in the hamster, testosterone accelerates functional recovery from hind limb paralysis following sciatic nerve injury in the rat. While the responses of spinal motoneurons to injury can differ from those of cranial motoneurons, in this case it appears that they share a similar response to the trophic actions of androgen. This is important in the context of designing therapeutic strategies for dealing with direct trauma to motoneurons resulting from both peripheral and central nervous system trauma, such as spinal cord injury.

Purpose: Until recently, there has been a limited amount of research comparing functional and anatomical recovery following nerve injury. Previous studies emphasizing anatomical recovery (such as axonal number) have shown that testosterone promotes regeneration in crushed and transected nerves. The purpose of this study was to assess the effect of testosterone on the functional recovery of the sciatic nerve follow-ing a unilateral crush injury. Methods: Young adult male Sprague-Dawley rats were injected daily with either 500 µg testosterone proprionate or vehicle alone. The recovery course was followed for six weeks using functional and behavioral testing. Behavioral tests included a footprint gait analysis (as a measure of motor function), response to a skin pinch, and warm water withdrawal (measures of sensory function). Results: Immediately following surgery, all tests indicated complete denervation to the leg distal to the crush site. Anatomical analysis revealed a 22 % increase in the number of axons in testosterone treated animals at 6 weeks post-crush, but no indication of differences in functional recovery. The results of behavioral testing indicated only minor differences in functional recovery as a result of testosterone treatment. Conclusion: The results indicate the need for a detailed comparison between anatomical regeneration and functional recovery. An increase in axon number alone may not be an accurate indicator of successful regeneration.

Fimbria-fornix lesions abolish the hippocampal electrophysiological activity time-locked to the theta rhythm and alter some functional characteristics of place cells. The present experiment investigated whether homotopic grafts of fetal septal cells can alleviate some of these alter-ations when combined with a polymeric hydrogel bridging a fimbria-fornix lesion-cavity. Eleven months after grafting surgery, unit recordings were obtained from hippocampal neurons of seven rats [two sham-operated (S), two lesion-only (L) and three grafted (G)] while they explored a radial maze. The lesions induced dramatic loss of hippocampal acetylcholinesterase(AChE)-positive reaction products. Surviving grafts were found in the three grafted rats and several AChE-positive processes could be observed in the polymeric hydrogel, as well as in the most dorsal portion of the hippocampal parenchyma. Of 168 recorded units, 132 were hippocampal interneurons (i.e., fired rapidly everywhere in the maze), and 36 were pyramidal place cells (i.e., fired only when the rat was in a specific location in the maze, the place field). The overall firing characteristics of either cell type were similar in S, L and G rats. However, while none of the interneurons recorded from L rats was found to fire rhythmically, a significant proportion of interneurons recorded from S and G rats had an activity pattern time-locked to the theta rhythm [S: 16/19 (84 %); G : 22/70 (31 %)]. In addition, the increase in firing activity observed in interneurons recorded from S rats when they were moving was disrupted in cells from L rats, but partially restored in cells from G rats. Concerning place cells, most (93 %) place fields in S rats were stable relative to extra-maze cues when the radial maze was rotated, while they followed the maze rotation in both L and G rats. Because of the low number of rats used, the present results should be considered with caution. Nevertheless, they indicate graft-induced recovery of some properties of hippocampal function following fimbria-fornix damage, and suggest that homotopic transplants of projection neurons may foster some func-tional recovery when provided with a biomaterial allowing the host or grafted neurons to cross the lesion cavity.

Object: This study evaluated the dose related effects of Cyclosporin A (CsA) alone and in combination with monoclonal antibodies (mAbs) directed against intercellular adhesion molecule-1 (ICAM-1) and the alpha subunit of leukocyte function-associated antigen (LFA-1 ) on peripheral nerve allograft rejection in a rat model. Methods: Nerve regeneration was assessed using gait analysis of returning hind limb function, histology, and morphometry. Results: Regeneration comparable to isograft controls and high dose CsA treatment groups was observed when mAbs were used in combi-nation with intermediate dose CsA. Intermediate dose CsA therapy without additional mAbs was insufficient to support this level of regeneration. Nerve allografts treated with high and low dose CsA demonstrated no increased benefit with the addition of mAb therapy. Conclusions: Thus, mAbs seem to have a dose dependent effect on immunosuppression when used in combination with CsA, and may have therapeutic promise as a rescue therapy when CsA levels fall or issues of toxicity become important.

Purpose: At present the mechanisms of ischemic or hypoxic tolerance are not fully understood at the cellular level. Methods: In order to further characterize the effects of conditioning hypoxia on the synaptic transmission in the hippocampal area CA1, rats were exposed to a moderate normobaric hypoxia for 8 h. Transverse hippocampal slices were prepared 1, 7 or 14 days after this conditioning hypoxia and evoked field potentials were recorded in the CA 1 region upon stimulation of the Schaffer collaterals before, during and up to 4 h after ischemia in vitro (hypoxia and reduced glucose). Results and Conclusions: The time to disappearance of the evoked potential during ischemia was significantly prolonged after seven, but not after one or 14 days in slices taken from conditioned animals. In addition the input/output (I/O) curves of evoked potentials were not altered 4 h after the ischemia. In contrast, the time to disappearance of the evoked potentials was shorter and the I/O curves were diminished in slices from control animals. Possible mechanisms of the protective effect are discussed.

The use of sex hormones as potential neurosteroids capable of enhancing neuronal repair and functional recovery is gaining some momentum in the experimental literature. Two very interesting papers are presented in this issue of Restorative Neurology and Neuroscience outlining the effects of testosterone treatment upon anatomical and functional recovery after sciatic nerve crush injuries.