Artificial lighting conditions and melatonin alter motor performance in adult rats.

Entrained circadian rhythms may modulate many behavioral activities of animals and humans. In the present study, we examined whether lighting conditions and melatonin treatment participate behaviorally in the entrainment of circadian rhythms in the rodent. In experiment one, Sprague-Dawley rats were introduced to the Rotorod test apparatus at nighttime or daytime and either with the lights on (4 lux) or in the dark. During nighttime tests, the exposure of rats to dark or light condition did not alter mean rev./min or length of times spent on the Rotorod. Interestingly, during daytime tests, animals exposed to light condition displayed significantly reduced mean rev./min (7.95 +/- 1.68), as well as length of time on the Rotorod (41.07 +/- 3.45 s) compared with their performance in the dark condition (mean rev./min, 11.16 +/- 1.52; length of time spent on the Rotorod, 66.94 +/- 6.15 s). In experiment two, treatment with melatonin (1.5 mg/kg, orally administered at 1 h prior to testing) in animals introduced to the daytime test with exposure to light condition, restored the rev./min (12.90 +/- 1.26) and the time spent on the Rotorod (63.21 +/- 2.73 s) to near normal levels. Thus, we demonstrated here that exposure of nocturnal animals to their preferred dark condition and treatment with melatonin could enhance motor coordination.

Sertoli cells decrease microglial response and increase engraftment of human hNT neurons in the hemiparkinsonian rat striatum.

Sertoli cells (SCs) provide immune protection and nutritive support to the developing germ cells in the testis. Sertoli cells have also been shown to provide immune protection to islets transplanted outside the testes. In this study, the ability of these cells to diminish the infiltration/activation of microglia into a neural graft implanted in the lesioned striatum of a hemiparkinsonian rat was investigated. Human neuron-like cells (hNT neurons) were implanted either alone or in combination with rat SCs. Three months later, the animals were sacrificed and immunohistochemistry was performed to determine the survival of the xenografted neurons as well as microglial infiltration/activation. Cotransplantation of the SCs with the hNT neurons increased graft survival and was associated with an increase in graft size. Furthermore, there were fewer microglia present in the grafted tissue of the cotransplantation groups. These results show that SCs retain their immunosuppressive ability even within the brain. As immune responses to grafted neural tissue within the central nervous system become better understood, this ability of the SCs to provide localized immunosuppression to the transplanted tissue may become more important. This is particularly true as the search for alternative sources of neural tissue to treat neurodegenerative diseases expands to encompass other species.

Sertoli cells enhance the survival of co-transplanted dopamine neurons.

One of the major issues in neural transplantation is the low survival rate (<5%) of transplanted dopamine (DA) neurons [3]. Recently it has been shown that it is possible to enhance the survival of these neurons, which in turn may decrease the amount of tissue that is required for each transplantation patient. The present paper demonstrates a novel approach for enhancing neuronal survival by co-transplantation of neuronal tissue with Testis-derived Sertoli cells (SC). This strategy could improve neuronal survival through the provision of trophic support.

Viability and survival of hNT neurons determine degree of functional recovery in grafted ischemic rats.

We recently reported behavioral improvements following intrastriatal transplantation of cryopreserved cultured human neuroteratocarcinoma-derived cells (hNT neurons) in rats with cerebral ischemia induced by occlusion of the middle cerebral artery. In the present study, the viability and survival of hNT neurons were evaluated immediately prior to the transplantation surgery and at 3 months post-transplantation in ischemic rats. Cryopreserved hNT neurons were routinely thawed, and trypan blue exclusion viability counts revealed 52-95% viable hNT neurons before transplantation. Monthly behavioral tests, starting at 1 month and extending to 3 months post-transplantation, revealed that ischemic animals that were intrastriatally transplanted with hNT neurons (approximately 40000) and treated with an immunosuppressive drug displayed normalization of asymmetrical motor behavior compared with ischemic animals that received medium alone. Within-subject comparisons of cell viability and subsequent behavioral changes revealed that a high cell viability just prior to transplantation surgery correlated highly with a robust and sustained functional improvement in the transplant recipient. Furthermore, histological analysis of grafted brains revealed a positive correlation between number of surviving hNT neurons and degree of functional recovery. In concert with similar reports on fetal tissue transplantation, we conclude that high cell viability is an important criterion for successful transplantation of cryopreserved neurons derived from cell lines to enhance graft-induced functional effects.

Bilateral fetal striatal grafts in the 3-nitropropionic acid-induced hypoactive model of Huntington's disease.

We investigated the 3-nitropropionic acid (3-NP)-induced hypoactive model of Huntington's disease (HD) to demonstrate whether fetal tissue transplantation can ameliorate behavioral deficits associated with a more advanced stage of HD. Twelve-week-old Sprague-Dawley rats were introduced to the 3-NP dosing regimen (10 mg/kg, i.p., once every 4 days for 28 consecutive days), and were then tested for general spontaneous locomotor activity in the Digiscan locomotor apparatus. All rats displayed significant hypoactivity compared to their pre-3-NP injection locomotor activity. Randomly selected rats then received bilateral intrastriatal solid grafts of fetal striatal (lateral ganglionic eminence, LGE) tissues from embryonic day 14 rat fetuses. Approximately 1/3 of each LGE in hibernation medium was infused into each lesioned host striatum. In control rats, medium alone was infused intrastriatally. A 3-mo posttransplant maturation period was allowed prior to locomotor activity testing. Animals receiving fetal LGE grafts exhibited a significant increase in locomotor activity compared to their post-3-NP injection activity or to the controls' posttransplant activity. Surviving striatal grafts were noted in functionally recovered animals. This observation supports the use of fetal striatal transplants to correct the akinetic stage of HD. To the best of our knowledge, this is the first study that has investigated the effects of fetal striatal transplantation in a hypoactive model of HD.

Neural transplantation as an experimental treatment modality for cerebral ischemia.

Cerebrovascular disease exemplifies the poor regenerative capacity of the CNS. While there are methods to prevent cerebral infarction, there is no effective therapy available to ameliorate the anatomical, neurochemical and behavioral deficits which follow cerebral ischemia. Focal and transient occlusion of the middle cerebral artery (MCA) in rodents has been reported to result in neuropathology similar to that seen in clinical cerebral ischemia. Using specific techniques, this MCA occlusion can result in a well-localized infarct of the striatum. This review article will provide data accumulated from animal studies using the MCA occlusion technique in rodents to examine whether neural transplantation can ameliorate behavioral and morphological deficits associated with cerebral infarction. Recent advances in neural transplantation as a treatment modality for neurodegenerative disorders such as Parkinson's disease, have revealed that fetal tissue transplantation may produce neurobehavioral recovery. Accordingly, fetal tissue transplantation may provide a potential therapy for cerebral infarction. Preliminary findings in rodents subjected to unilateral MCA occlusion, and subsequently transplanted with fetal striatal tissue into the infarcted striatum have produced encouraging results. Transplanted fetal tissue, assessed immunohistochemically, has been demonstrated to survive and integrate with the host tissue, and, more importantly, ameliorate the ischemia-related behavioral deficits, at least in the short term. Although, this review will focus primarily on cerebral ischemia, characterized by a localized CNS lesion within the striatum, it is envisioned that this baseline data may be extrapolated and applied to cerebral infarction in other brain areas.

Free radical damage and oxidative stress in Huntington's disease.

Bioenergetic defects and oxidative stress may be critical links in an excitotoxic mechanism of neuronal death. Oxidative stress, a condition describing the production of oxygen radicals beyond a threshold for proper antioxidant neutralization, has been implicated as a pathologic condition in several neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. In addition, oxygen radicals are known to be important mediators in acute pathologies, in the theory of senescence, cancer, as well as our healthy immune system. Although free radicals may have a special chemical nature which allows them to perform important cellular functions, they are a damaging entity whose reactivity may play a part in the development of cellular compromises that can kill a neuron. In this review, the free radicals in biological systems, the defense systems against them, and the damaging interactions, i.e., oxidative stress, which they confer are discussed. The descriptions provided raise the hypothesis that an imbalance between the production and removal of radicals would be abrasive on a neuron. Accordingly, the neurodegeneration initially caused by gene mutation in Huntington's disease may be further worsened by free radical damage underlied by oxidative stress. This article reviews existing data on the free radical damage and the oxidative stress, which are primarily directed towards Parkinson's disease and Alzheimer's disease, and whenever possible relates such mechanisms to Huntington's disease.