Nicotine for the treatment of Tourette's syndrome.

Recent evidence has demonstrated that nicotine may obtund the symptoms of Tourette's syndrome (TS). TS is a neuropsychiatric disorder characterized by motor and vocal tics, obsessions and compulsions, and frequently with impulsivity, distractibility, and visual-motor deficits. While neuroleptics, such as haloperidol, are most effective for treatment of the motor and vocal tics of TS, these medications have many side effects. In this article, we review the evidence, consistent with findings in animals, that administration of nicotine (either 2 mg nicotine gum or 7 mg transdermal nicotine patch) potentiates the therapeutic properties of neuroleptics in treating TS patients and that a single patch may be effective for a variable number of days. These findings suggest that transdermal nicotine could serve as an effective adjunct to neuroleptic therapy for TS.

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.

Autologous transplantation of adrenal medulla in Parkinson's disease. 18-month results.

Eighteen of 19 patients who underwent autologous adrenal medullary transplantation to the right caudate nucleus have been followed up for 18 months. During the course of this study, a statistically significant improvement was noted in percent "on" time, percent "on" time without dyskinesia, activity of daily living (ADL) scores during the "on" stages, and ADL, motor, and Schwab-England scores during the "off" stages. Benefits tended to be maximal at 6 months and to gradually lessen thereafter, although statistically significant improvement in comparison with baseline was still present at 18 months for ADL, motor, and Hoehn-Yahr scores during the "off" stages. Almost all parameters had deteriorated by 18 months compared with 12 months, including those remaining significantly improved in comparison with baseline. These patterns were similar for each of the three participating centers. Complications were largely restricted to the perioperative period.

Cell transplantation for central nervous system disorders.

Initially, the specific aim of transplantation studies was to investigate the regenerative capabilities of the mammalian nervous system. From this underlying impetus, a myriad of knowledge, spanning from molecular biology to neurobiology, has enhanced our understanding of regeneration and the applicability of fetal tissue transplantation in treating various neurodegenerative diseases. Current evidence suggests that transplantation of fetal neural tissue ameliorates the neurobiological and behavioral changes observed in animal models of central nervous system (CNS) disorders. In light of numerous basic science studies, clinical trials have begun to evaluate the potential of neural transplantation in treating human diseases. Indeed, modest progress has been reported in the treatment of Parkinson's disease. However, whereas fetal tissue transplantation has reached considerable success, it has also been observed to produce either no beneficial effects, magnify existing behavioral abnormalities, or even produce a unique constellation of deficits. Thus, while the prospects are promising, further investigations aimed at improving and refining existing transplantation paradigms are warranted before neural transplantation techniques can be of widespread value. This review article attempts to provide an overview of the neuroanatomical, neurochemical, and behavioral effects produced by transplanted fetal tissue in several animal models of CNS disorders. We have attempted to present both positive and adverse effects and to critically analyze the suitability of neural transplantation as a therapy for the various neurological disorders. In addition, alternative approaches, including the use of encapsulated neural tissue implants and genetically engineered cell lines along with their clinical potential, are discussed when appropriate.

Asymmetrical behavior in rats following striatal lesions and fetal transplants: the elevated body swing test.

Animals with unilateral neurotoxic lesions in the striatum exhibit a stereotypical biased rotational behavior in response to dopamine agonists. We recently argued that the rotational test may be subject to sensitization effects of the drug. Accordingly, we proposed the drug-free elevated body swing test (EBST) as an alternative behavioral index of motor asymmetry in striatal lesioned animals. EBST involves elevating the animal from the ground by holding its tail and simply recording the number of swings to either side made by the animal over 30 s. We previously reported that Sprague-Dawley, male 8-week-old rats, intrastriatally lesioned with 500 nanomoles of 3-nitropropionic acid or 225 nanomoles of quinolinic acid, exhibit biased swing activity at 7, 14, 21 and 28 days post-lesion. In the present study, we extended the efficacy of the EBST in measuring the recovery of motor function following fetal striatal transplants. At 2 months post-lesion, lesioned animals which show 70% or higher biased swing activity were transplanted with rat fetal striatal lateral eminence (16-day-old gestational age). When tested in the EBST at 1 and 3 months post-transplant, these transplanted animals displayed normalization of the biased swing activity. In contrast, animals transplanted with medium alone continued to exhibit a biased swing activity. The present study thus extends our previous EBST data to include successful behavioral characterization by EBST of recovery of motor function in lesioned animals receiving fetal transplants.

Age-dependent neurobehavioral responses by young and mature adult rats to systemic kainic acid.

Neurobehavioral effects caused by the excitotoxin kainic acid (KA) have been characterized by convulsions including 'wet dog shakes' (WDS) with accompanying hippocampal degeneration in experimental animals. Accordingly, this model has been proposed for putative excitotoxin-mediated disorders, such as the temporal lobe epilepsy. There have been reports on age-dependent neurobehavioral effects of KA; however, little is known about possible correlations between neuropathology and behavioral responses to KA. The present study demonstrates that mature adult rats (12 months old) injected subcutaneously (s.c.) with KA (12 mg/kg) had severer damage to the hippocampal formation, i.e. CA3 region, compared with KA-treated young adult rats (2 months old). The mature adult animals also exhibited an earlier onset of WDS, a significantly higher number of WDS (P > 0.01), and severer convulsions compared with young adult rats. These findings indicate a positive correlation between KA-induced hippocampal damage and behavioral responses in young and mature adult rats.

Intrastriatal 3-nitropropionic acid: a behavioral assessment.

Systemic injections of 3-nitropropionic acid (3-NP) in Sprague-Dawley rats have led to (1) hypoactivity that resembles juvenile onset and advanced Huntington's disease (HD), and (2) impairment in contextual retention of passive avoidance. Since it has been established that 3-NP exerts its primary effects in the striatum, we selected intrastriatal injections to more thoroughly understand the direct behavioral effects of 3-NP. Each 14-week old rat received bilateral intrastriatal injections of one of the following: 500 and 750 nmol of 3-NP or vehicle (0.9% saline). At seven days following surgery, the animals were tested for spontaneous locomotor behavior and passive avoidance behavior. Results revealed deficits in both locomotor activity and passive avoidance learning. The animals injected with 500 and 750 nmol of 3-NP were significantly hypoactive compared with control animals. Similarly, the 2 groups of animals were severely impaired in the retention of passive avoidance compared with control. The 3 groups, however, did not differ in their acquisition of this learning task. Macroscopic analyses of brains of these animals revealed that 500 and 750 nmol of 3-NP caused severe loss of neuronal cell bodies and marked glial infiltration in the medial aspect of the striatum. Larger lesions showed a necrotic cavity at the injection site. In comparison with systemic administration of 3-NP, intrastriatal injections resulted in more profound hypoactivity, greater loss of passive avoidance retention, and more severe striatal damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporine-A increases spontaneous and dopamine agonist-induced locomotor behavior in normal rats.

Cyclosporine-A (CsA) has been increasingly used as an immunosuppressant concomitant with neural transplantation treatment for different degenerative disorders. However, the possible role that CsA itself may have in the recovery of transplant patients is not known. Some investigators have argued that clinical improvement following transplantation (e.g., myoblast) may be confounded by CsA administration. The present study was conducted to delineate CsA-induced behavioral alterations. Four groups of normal 5-wk old Sprague-Dawley rats (n = 8 per group) were utilized in two separate experiments. In both experiments, two groups of animals were used; each group either received daily injections of 15 mg/kg of CsA or olive oil for 32 days (experiment 1) and 21 days (experiment 2). Animals in both experiments were subsequently tested for nocturnal locomotor behavior. Animals in experiment 2 were further tested in passive avoidance task, motor coordination, and amphetamine-induced locomotor activity. Results demonstrated that CsA-treated animals were significantly hyperactive compared to controls across the 12-h nocturnal activity periods and in amphetamine-induced locomotor activity. No significant differences between the CsA- and vehicle-treated animals were observed in passive avoidance or in motor coordination. Postmortem analyses of dopamine and its metabolites in the striatum and olfactory tubercle did not show any significant differences between the CsA- and the vehicle-treated groups. In summary, CsA significantly increased nocturnal spontaneous and amphetamine-induced locomotor behavior, but the neurochemical correlates for these effects need to be investigated. In addition, while the present study demonstrated that CsA induced motor alterations, any possible effects CsA may have on neurological or dystrophic patients with motor dysfunctions remain to be determined.

The effects of taurine on hNT neurons transplanted in adult rat striatum.

Taurine acts as an antioxidant able to protect neurons from free radical-mediated cellular damage. Moreover, it modulates the immune response of astrocytes that participate in neurodegenerative processes. The objective of this study was to examine whether taurine can prevent or attenuate the host inflammatory response induced by the xenotransplantation of neurons derived from the human teratocarcinoma cell line (hNT neurons). Male Sprague-Dawley rats were treated IP with either saline or taurine. Animals from both groups were perfused on the 4th or 11th day and the saline or taurine was administered from the start of the study until the day prior to sacrifice. The brains were processed immunohistochemically using antibodies against glial fibrillary acidic protein (GFAP), microglia (OX42), and human nuclear matrix antigen (NuMA). In the saline group, NuMA labeling revealed small grafts on the 4th day and no surviving cells on the 11th day. However, in the group that received taurine there were surviving grafts at both time points. Strong immunoreactivity for GFAP and OX42 was detected in the saline group surrounding the transplant. These effects were reduced in animals receiving taurine. Taken together, these results demonstrated that taurine was able to facilitate graft survival and attenuate the immune response generated by the xenograft.

Behavioral pathology induced by repeated systemic injections of 3-nitropropionic acid mimics the motoric symptoms of Huntington's disease.

Huntington's disease is a progressive neurodegenerative disorder associated with severe degeneration of basal ganglia neurons, especially the intrinsic neurons of the striatum, and characterized by involuntary abnormal choreiform movements and progressive dementia. With the discovery of the gene underlying HD, genetic therapy may be the next logical step towards finding a cure, but no such treatment is currently available. Animal models that closely mimic the neurobiological and clinical symptoms of the disease may offer an alternative approach for the development of new therapies. We report that systemic administration of 3-nitropropionic acid, an inhibitor of the mitochondrial citric acid cycle, results in a progressive locomotor deterioration resembling that of HD. We further demonstrate that manipulating the time course of 3-nitropropionic acid injections leads to sustained hyperactivity (early HD) or hypoactivity (advanced HD). These data suggest that this animal model can be used to test experimental treatments for HD across different stages of the disease.

Asymmetrical motor behavior in rats with unilateral striatal excitotoxic lesions as revealed by the elevated body swing test.

Severe degeneration of basal ganglia neurons, particularly the intrinsic neurons of the striatum, is the major underlying neuropathology implicated in clinical attributes of Huntington's disease (HD). The excitotoxin-lesioned striatum provides a useful model for evaluating behavioral parameters of HD. Animals with unilateral excitotoxic lesions exhibit asymmetrical rotational behavior in response to dopamine agonists, such as apomorphine. However, the observed behavior is a pharmacological reaction, and subject to sensitization effects. A behavioral test using undrugged animals may demonstrate a more natural response of the animals to the lesion effects. Recently, we have developed the 'drug-free' elevated body swing test (EBST), and demonstrated that hemiparkinsonian rats exhibited significant biased swing activity. In the present study, we observed that animals with unilateral intrastriatal 3-nitropropionic acid or quinolinic acid lesions displayed a significant biased swing activity with the direction ipsilateral to the lesioned side of the brain. This ipsilateral swing corresponded to the ipsilateral rotational behavior exhibited by the lesioned animals when challenged with apomorphine. The present results demonstrated that the EBST is a sensitive measure for characterizing asymmetrical behavior in animals with striatal lesions.

Systemic 3-nitropropionic acid: long-term effects on locomotor behavior.

Systemic administration of 3-nitropropionic acid (3-NP) results in striatal atrophy by irreversibly inhibiting the citric acid cycle, and thereby resulting in cellular ATP depletion. The neuropathological outcome following 3-NP injections is thought to resemble that seen in Huntington's disease (HD) [1]. The current study administered systemic injections in 6- and 10-week-old rats of low-dose 3-NP every other 4 days for a period of 28 days in order to investigate the effects on locomotor behavior and striatal D1 dopamine receptor binding. Experimental and control animals received intraperitoneal injections of 3-NP (10 mg/kg in 0.9% saline) and 0.9% saline, respectively. Animals were tested behaviorally prior to the first and after the last 3-NP administration. Brains were then removed and striatal tissue samples were analyzed for D1 dopamine receptor binding using [3H]SCH23390. Behaviorally, 6-week-old injected animals developed bradykinesia with no signs of stiffness or rigidity, while 10-week-old injected animals displayed an uncoordinated gait, stiffness and ventral recumbency with hind limbs extended in a rigid or fixed position. These visual observations of hypoactivity were supported by a significant decline in both experimental groups' locomotor activity as measured by Digiscan monitors. Furthermore, [3H]SCH23390 specific binding to D1 dopamine receptors revealed a small but significant decrease in 10-week-old injected animals compared to controls. These results demonstrate that both 6- and 10-week-old rats do exhibit behavioral alterations after long-term 3-NP administration, however the former may not show accompanying gross D1 receptor changes.

Substance P containing polymer implants protect against striatal excitotoxicity.

The present study examined whether substance P (Sub P) could protect against quinolinic acid (QA)-induced lesions of the striatum, as measured by a loss of striatal D1 dopamine receptors. Sub P was extruded into Evac polymer rods for slow release. One 4 mm rod segment was implanted unilaterally into the striatum of each rat. One week later, animals received a striatal injection of QA (50, 75 or 100 nmol/microliters) medial to the implanted rod. Controls received QA alone. Three weeks later, there was a dose-dependent loss of D1 receptors following QA. Sub P rods protected the striatum from QA-induced D1 receptor loss at this time. These results support the neuroprotection role of Sub P on excitotoxicity.

Behavioral effects of fetal neural transplants: relevance to Huntington's disease.

Animal models of Huntington's disease (HD) and other neurological disorders have proven useful for examining the anatomical, neurochemical, and behavioral alterations in these diseases. Investigators have taken advantage of new excitotoxic models that appear to successfully simulate the neurobiological and behavioral characteristics of HD with remarkable homology. Selective excitotoxic compounds allow for a more precise and controlled lesion with which to examine the relationship between striatal damage and behavioral abnormalities. In addition, these models provide new approaches for developing and testing various treatments for HD. Fetal neural tissue transplanted into the excitotoxin-lesioned animal can integrate with the host brain and promote neurochemical and functional recovery. Neural grafting paradigms may be viewed as potential therapies for treating neurodegenerative diseases and as aids in deciphering the regenerative mechanisms of the central nervous system. Further research is necessary, however, to determine the negative and positive effects of neural transplantation. In addition, existing behavioral models need to be refined to allow for better evaluation of the subtle topographic changes in behavior resulting from fetal tissue transplantation.

hNT neurons delay onset of motor deficits in a model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease that manifests as a progressive muscular weakness leading to paralysis and death. Because of the diffuse nature of the motor neuron death, this disease is not considered a good candidate for treatment through neural transplantation. The purpose of this study was to show that transplantation of human neuron-like cells (hNT neurons) into the spinal cord of a transgenic ALS mouse model would improve motor deficits. The hNT neurons were transplanted bilaterally into L4-L5 spinal cord of the transgenic mice ( approximately 8 weeks of age), and the animals were evaluated on health and behavioral measures. The animals were perfused, and immunohistochemistry was performed to identify the transplanted cells. Transplantation of the hNT neurons into the spinal cord delayed the onset of motor behavioral symptoms. This was the first demonstration that even localized transplantation of neural cells directly into the parenchyma could improve motor function in an ALS model. Further study is needed to delineate the mechanism underlying these effects. This therapeutic approach has the potential to restore neural transmission, thereby improving quality of life for the ALS patient and possibly extend life expectancy.

Systemic 3-nitropropionic acid: behavioral deficits and striatal damage in adult rats.

Previous animal studies have demonstrated that systemic administration of 3-nitropropionic acid (3-NP) leads to neuropathological changes similar to those seen in Huntington's disease (HD). Recently, we reported hypoactivity in 6- and 10-week old rats treated with systemic 3-NP (IP, 10 mg/kg/day) once every 4 days for 28 days. Although these behavioral results seem to differ from the observed hyperactivity in most excitotoxic models of HD, 3-NP may provide a better model of juvenile onset and advanced HD. In the present study, older rats were similarly treated with 3-NP to further characterize the reported age dependency of striatal neuronal death caused by 3-NP. Hypoactivity was observed in 14- and 28-week old rats with the latter demonstrating more profound features. The present study also provided the first direct evidence of a 3-NP effect on passive avoidance behavior. Experimental and control animals showed no significant difference in daytime acquisition and retention of a passive avoidance task. However, when the retention tests were conducted during the night time (in contrast to previous daytime tests), 3-NP-treated animals exhibited significant retention deficits. In addition, the neuropathological effects of 3-NP were determined by Nissl, AChE and NADPH-diaphorase histochemistry. Metabolic activity was studied using cytochrome oxidase activity as an index. Results revealed striatal glial infiltration, loss of intrinsic striatal cholinergic neurons, but some sparing of large AChE positive neurons, minimal damage of NADPH-diaphorase-containing neurons, and very slight, if any, alterations in cytochrome oxidase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Implications of neurological rehabilitation for advancing intracerebral transplantation.

Neurological rehabilitation involves the systematic presentation of environmental stimuli and challenges that enable the patient to learn strategies for minimizing their disabilities. Rehabilitation therapy of transplant recipients may be an important factor in enhancing the efficacy of the transplanted organ or tissue to promote functional recovery. Laboratory research and clinical trials on neural transplantation, as an experimental treatment for neurological disorders (e.g., Parkinson's disease, Huntington's disease, and cerebral ischemia), have focused primarily on devising effective surgical implantation strategies with little attention devoted to the interaction between environmental factors and restorative neurosurgery. Exercise training as part of neurological rehabilitation may be an important factor for neural transplantation therapy for Parkinson's disease. Rehabilitation providers are particularly well placed to provide the environment and the support to optimize the behavioral functioning of neural transplant patients in learning to use the new grafted tissue.

Aneurysmal bone cyst of the odontoid process: case report.

Aneurysmal bone cysts (ABCs) are relatively uncommon, benign lesions. Fully 50% occur in long bones and 20% in the vertebral column, mostly in patients under 20 years of age. We report a case of an ABC in the odontoid process of a 74-year-old who sought treatment for pain and myelopathy. This is the first case reported of an ABC of the odontoid process.

Prolactin-secreting adenoma in a myasthenic patient.

A case of pituitary adenoma in a patient with myasthenia gravis as well as hypothyroidism, adrenocortical hypopituitarism, and diabetes mellitus is presented. The favorable response of this man's myasthenic symptoms after removal of the adenoma and a possible relationship between the symptomatic expression of myasthenia and a functional hypothalamo-hypophyseal axis are discussed. A link between myasthenia gravis and other autoimmune phenomena is hypothesized.

Bilateral facet to spinous process fusion: a new technique for posterior spinal fusion after trauma.

A variety of options exist for the treatment of fracture/dislocation of the cervical spine, including prolonged traction immobilization, immobilization in an external device, and open surgical fusion. In cases of facet dislocation and flexion/compression injuries, the authors have found that surgical fusion is the most useful. However, in cases of facet fracture or disruption of the posterior neural arch, routine interspinous wiring techniques do not provide adequate rotational stability and may allow postsurgical redislocation before bony fusion. For these cases, a new technique using bilateral facet to spine wire loops has been developed. In the 25 cases reported here, the technique provided excellent stability against anterior horizontal displacements and rotational dislocations despite unilateral or bilateral facet fracture or disruption of the posterior neural arch.