Restorative Neurology and Neuroscience

Administration of gangliosides accelerates recovery of function after entorhinal cortex lesions on open field activity and learned spatial alternation tasks. In the present study, we examined whether GM1 ganglioside might enhance recovery from bilateral entorhinal cortex lesions on a differential reinforcement of low-rate responding tak with a 20 sec delay (DRL-20) as well as on open field activity. Optical densitometry measurements were taken to assess sprouting by the acetylcholinesterase-containing septodentate pathway. Eighteen rats were assigned to sham/GM1, lesion/GM1, or lesion/saline conditions. After preoperative training and testing, the rats received surgery and were then tested post-operatively for thirty days. GM1 injections (20 mg/kg) were given beginning the day before surgery through day 5 postsurgery and then on alternating days. Relative to the lesion/saline group, rats in the lesion/GM1 group showed enhanced recovery on the DRL-20 and the open field tasks. The lesion/GM1 group had significantly less septodentate sprouting than the lesion group treated with saline. GM1 treatment may be facilitating recovery from bilateral entorhinal lesions by reducing the trauma of injury and denervation, reducing heterologous sprouting, or both.

The tuberomammillary nucleus (TM) is the only known neuronal cell group in the brain which contains histamine. There is evidence for a reciprocal relationship between the effects of histamine and dopamine on behavior. A unilateral lesion of dopamine cells in the Substantia Nigra (SN) results in asymmetrical behavior, and recovery from this asymmetry was previously found to be associated with asymmetrical changes in the nigro-striatal projection as determined by anatomical tracing technique. In view of the apparent opposing interaction between the TM and the SN, we examined whether the tuberomammillary-striatal projection also shows changes after a unilateral lesion of the SN. Rats had 6-OHDA injected into one substantia nigra and were tested for behavioral asymmetry over a 15 day period. Horseradish peroxidase (HRP) was then deposited in the caudate-putamen (CPU) ipsilateral to the lesion. Controls devoid of a lesion had the tracer deposited in either the right of left CPU. More HRP-labeled cells were found in the anterior part of TM ipsilateral to the lesion in the animals which failed to recover from lesion-induced asymmetry in turning behavior, as compared to normal controls or animals which showed behavioral recovery. The labeled cells in the anterior part of the ipsilateral TM were smaller in animals examined 15 days after the lesions than in the control animals. The results indicate an increase in HRP uptake or transport in the anterior part of the tuberomammillary-striatal projection predominantly ipsilateral to the lesion in animals which failed to recover from lesion induced asymmetry. Previously, we had found an opposite effect in the nigro-striatal projection, namely an increase in HRP uptake or transport only in animals which recovered from their lesion induced asymmetry. The results are discussed in terms of the evidence for a reciprocal relationship between the TM- and SN-striatal systems.

The present aimed to identify the origin of medullary and upper cervical respiratory neurons regenerating their axons into the peripheral nerve grafts in adult rats. We employed an antidromic activation technique and a retrograde horseradish peroxidase (HRP) tracing method for determining the origins of the regenerating axons. Autologous segments of the common peroneal nerve were successfully implanted ventrolaterally into the proximal cut end of the C2 spinal cord hemisection (n = 24). Two to 5 months after implantation, spontaneous multi-unit discharges were recorded in all grafts; respiratory-related discharges in 21 (87.5%) grafts; and non-respiratory discharges in 3 (12.5%) grafts. The respiratory discharge patterns were similar to those for normal respiratory efferent neurons in rats. After the recordings were completed, 5 of 182 respiratory units explored in the medullary ventral respiratory cell group (VRG) neurons were antidromically activated by electrical stimulation of the grafts (n = 15). The estimated axonal conduction velocities ranged from 5.6 to 7.4 (mean 6.7) m/s. Retrograde horseradish peroxidase (HRP) labelings applied to the distal cut end of the grafts (n = 13) revealed that HRP-labeled cells were located, predominantly ipsilaterally, in the brainstem up to 5-10 mm distant from the implanted site. Some HRP-labeled cells were observed in the region of the nucleus ambiguus where many respiratory neurons exist. These results demonstrate that peripheral nerve grafts implanted in the C2 segment can induce axonal regeneration of medullary VRG neurons conveying funcional efferent signals.

The development of tolerance to and dependence on BDZs was investigated by monitoring locomotor activity in mice. Alprazolam (6 mg/kg twice daily s.c.) or solvent were administered over 12 days. The treatment schedule at least 50% BDZ receptor occupancy throughout treatment. Receptor occupancy half-lives were determined to be 2.6 hrs and 4.8 hrs. after cessation of 4 and 12 days of alprazolam administration, respectively. To assess if the tolerance to and dependence on alprazolam were due to repeated exposure of mice to the experimental set-up, some groups of mice were tested repeatedly, while other groups were subjected only to a single exposure. The observed locomotor activity, measured as horizontal activity and total distance travelled, indicated that the development of tolerance and of withdrawal symptoms to alprazolam is not related to repeated exposure of the mice to the experimental set-up, but is due to changes in function of the GABAa receptor.

Injury to immature motoneurons results in extensive nerve cell death. Avulsion injury in adult animals has a similar effect. Rescuing injured neurons from degeneration and death is a prerequisite for succesful functional recovery. Here, we have explored the possible survival promoting effect of the immunosuppressant agents FK506 and cyclosporin A, the calcium channel blocker nimodipine as well testosterone on axotomized neonatal facial motoneurons. In addition, we examined the effect of cyclosporin A and Nimodipine, a calcium channel blocker, on survival of adult motoneurons following hypoglossal nerve avulsion. FK506 and cyclosporin A were administered intraperitoneally, testosterone intramuscularly and Nimodipine via the food. After the appropriate postoperative survival periods, the number of surviving facial or hypoglossal motoneurons respectively was calculated. FK506 and Cyclosporin A were found to enhance facial motoneuron survival following neonatal axotomy. Cyclosporin A and Nimodipine were found to promote motoneuron survival in adult rats after hypoglossal nerve avulsion. Nimodipine possibly also reduced motoneuron death in neonatal rats twenty-one days after facial nerve transsection, but failed to rescue motoneurons in neonatal rats during the first seven days after nerve injury. Treatment with testosterone was ineffective in preventing neonatal facial motoneurons from axotomy-induced death at seven days postaxotomy. The restults indicate that motoneuron degeneration can be counteracted to a large extent by immunosuppressant agents as well as by calcium channel blockers. Taken together with findings form previous studies, we conclude that motoneuron survival following axotomy can be promoted by a variety of endogenous and exogenous molecules acting on different cellular mechanisms.

Neural cell adhesion molecule L1 is a member of the immunoglobulin superfamily; it plays an important role in neurite outgrowth in vitro. We present evidence that the transected optic nerve in adult rats was promoted to regenerate by transplanted L1-expressing cells that were embedded in the Matrigel matrix. To obtain the maximum effects, a very careful operative procedure by which both stumps remained attached and the blood supply was preserved was essential. Visual evoked potential was partially recovered and traced fibers were seen to pass through the lesion site 7 weeks after optic nerve transection. Immunohistochemical analysis demonstrated that neurofilament-positive fibers were present around the site of experimental lesion. Our in vivo study demonstrated that L1 promoted the regeneration of the lesioned optic nerve in rats under strictly controlled environmental conditions.

This study examined the effects of chronic GM1 ganglioside administration on the evolution of cognitive and motor deficits in monkeys exposed to low doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over an extended period of time. Monkeys were administered low doses of MPTP for 26 weeks. Once stable cognitive deficits and minimal motor deficits were observed, animals were randomized to saline (N = 2) or GM1 ganglioside (N = 3) treatment groups. Treatments were administered for 90 weeks concurrent with continued low dose MPTP administration. During the first phase of the study (treatment 1-31), GM1 administration ameliorated cognitive deficits and protected against further cognitive decline. Cognitieve deficits worsened in saline-treated animals during this period. In the second phase of the study (weeks 32-52) MPTP dose were increased to enhance the severity of the parkinsonism. GM1-treated animals had delayed onset of motor deficits and a continued preservation of cognitive function. Cognitive and motor function declined in the saline-treated group. In the final phase of the study (weeks 53-90), MPTP doses were lowered back to the levels used during the intial phase of study. GM1-treated animals had significant recovery of motor function, while motor and cognitive function continued to be severely impaired in the saline-treated group. These results suggest that chronic GM1 treatment could be useful in the long-term treatment of Parkinson's disease.