Mecamylamine effects on haloperidol-induced catalepsy and defecation.

Recent clinical experience with Tourette syndrome (TS) patients suggests that the nicotinic receptor antagonist, mecamylamine (Inversine), may be a useful adjunct to neuroleptic therapy for controlling tic symptom. This is consistent with previous preclinical findings demonstrating that mecamylamine can potentiate the cataleptic effects of neuroleptics in rats. However, these earlier preclinical studies employed high doses (1-2.5 mg/kg) of mecamylamine that may not be clinically relevant since human doses of mecamylamine used to treat TS have been much lower (0.03-0.1 mg/kg). In order to test the potential therapeutic properties of mecamylamine preclinically, we conducted catalepsy experiments in rats employing both a low and high dose of mecamylamine in combination with haloperidol. Sixty-four male Sprague Dawley rats were randomized into four treatment groups (n = 16/group). Each rat received an injection of either saline or mecamylamine (0.1 or 3.0 mg/kg s.c.) followed one hour later with a second injection of either saline or haloperidol (0.4 mg/kg s.c.). The bar test was used to measure duration of catalepsy at 3 hrs following the second injection. The results demonstrated that only the mecamylamine treated rats showed statistically significant haloperidol-induced catalepsy when measured at 3 hrs. In addition, haloperidol-induced defecation was not affected by the 0.1 mg/kg mecamylamine dose, but completely abolished by the 3.0 mg/kg dose. These findings suggest that a clinically relevant dose of mecamylamine (0.1 mg/kg) can affect the duration of haloperidol-induced catalepsy without having significant effects on gastrointestinal function.

Taurine increases rat survival and reduces striatal damage caused by 3-nitropropionic acid.

Taurine acts as an antioxidant protecting neurons from free radical-mediated cellular damage. 3-nitropropionic acid (3-NP) inhibits energy metabolism, initiating oxidative stress. With the objective to examine whether taurine can protect glia and neurons from damage produced by 3-NP, male Wistar and Sprague-Dawley rats were treated with either (1) saline, (2) taurine (3) 3-NP and saline, or (4) 3-NP and taurine for 4 days. Survival was determined and brains were processed immunohistochemically. Large striatal lesions and increased GFAP, SOD, and taurine immunoreactivity were detected in the 3-NP group when compared with control groups. In contrast, animals receiving 3-NP and taurine exhibited less GFAP, SOD, and taurine immunoreactivity, along with increased survival rates. Results indicate that taurine treatment after 3-NP administration protects the striatum from damage.

Intraspinal implantation of hNT neurons into SOD1 mice with apparent motor deficit.

INTRODUCTION: The aim of this study was to determine the effect of hNT neuron transplants on motor neuron function in SOD1 (G93A) mice when motor deficits were already apparent. METHOD: The hNT neurons were implanted into L(4)-L(5) segments of the ventral horn spinal cord of mice at 15-16 weeks of age: either G93A mice, transgenic mice carrying the normal allele for human SOD1 gene (hTg), or control wild type mice (wt). Behavioral tests (rotorod, beam balance, extension reflex, footprint) were performed prior to transplantation and at weekly intervals afterwards. RESULTS: HNT neuron transplantation in the SOD1 mice delayed disease progression for 3-4 weeks, although lifespan was not affected. CONCLUSION: These results suggest that hNT neuron transplantation may be a promising therapeutic strategy for ALS in the later phase of the neurodegeneration.

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.

A critical appraisal of the reporting of the National Acute Spinal Cord Injury Studies (II and III) of methylprednisolone in acute spinal cord injury.

From the beginning, the reporting of the results of National Acute Spinal Cord Injury Studies (NASCIS) II and III has been incomplete, leaving clinicians in the spinal cord injury (SCI) community to use or avoid using methylprednisolone in acute SCI on the basis of faith rather than a publicly developed scientific consensus. NASCIS II was initially reported by National Institutes of Health announcements, National Institutes of Health facsimiles to emergency room physicians, and the news media. The subsequent report in the New England Journal of Medicine implied that there was a positive result in the primary efficacy analysis for the entire 487 patient sample. However, this analysis was in fact negative, and the positive result was found only in a secondary analysis of the subgroup of patients who received treatment within 8 hours. In addition, that subgroup apparently had only 62 patients taking methylprednisolone and 67 receiving placebo. The NASCIS II and III reports embody specific choices of statistical methods that have strongly shaped the reporting of results but have not been adequately challenged or or even explained. These studies show statistical artifacts that call their results into question. In NASCIS II, the placebo group treated before 8 hours did poorly, not only when compared with the methylprednisolone group treated before 8 hours but even when compared with the placebo group treated after 8 hours. Thus, the positive result may have been caused by a weakness in the control group rather than any strength of methylprednisolone. In NASCIS III, a randomization imbalance occurred that allocated a disproportionate number of patients with no motor deficit (and therefore no chance for recovery) to the lower dose control group. When this imbalance is controlled for, much of the superiority of the higher dose group seems to disappear. The NASCIS group's decision to admit persons with minor SCIs with minimal or no motor deficit not only enables statistical artifacts it complicates the interpretation of results from the population actually sampled. Perhaps one half of the NASCIS III sample may have had at most a minor deficit. Thus, we do not know whether the results of these studies reflect the severely injured population to which they have been applied. The numbers, tables, and figures in the published reports are scant and are inconsistently defined, making it impossible even for professional statisticians to duplicate the analyses, to guess the effect of changes in assumptions, or to supply the missing parts of the picture. Nonetheless, even 9 years after NASCIS II, the primary data have not been made public. The reporting of the NASCIS studies has fallen far short of the guidelines of the ICH/FDA and of the Evidence-based Medicine Group. Despite the lucrative "off label" markets for methylprednisolone in SCI, no Food and Drug Association indication has been obtained. There has been no public process of validation. These shortcomings have denied physicians the chance to use confidently a drug that many were enthusiastic about and has left them in an intolerably ambiguous position in their therapeutic choices, in their legal exposure, and in their ability to perform further research to help their patients.

Early aneurysm recurrence after technically satisfactory Guglielmi detachable coil therapy: is early surveillance needed? Case report.

Guglielmi detachable coil (GDC) therapy was initially intended as a treatment for select patients harboring aneurysms deemed to be at high risk for clip ligation. As experience with the technique has grown, many centers are now offering GDC therapy as a primary treatment to patients who are also good surgical candidates. The authors report a case in which a ruptured anterior communicating artery aneurysm recurred within 2 weeks of a technically satisfactory GDC procedure. The patient subsequently underwent successful surgery for clip ligation of the lesion. This is the earliest reported recurrence of an aneurysm after angiographically confirmed successful GDC therapy and underscores the need for performing early control angiography in patients undergoing this procedure.

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.

Rigid occipitocervical fusion.

OBJECT: Despite 50 years of neurosurgical experience, occipitocervical fusion continues to present a technical challenge to the surgeon. Traditional nonrigid techniques applied in the occiput and cervical spine often fail secondary to postsurgical cranial settling or rotational deformity. Unlike widely used nonrigid and semirigid techniques, rigid fixation of the craniocervical junction should allow correction of deformity in any plane, provide immediate stability without need for external orthosis, and prevent cranial settling. METHOD: Since 1992, the senior author (D.W.C.) has used a rigid plate and screw fixation system for occipitocervical fusions. The technique proved to be more difficult than expected, and the procedure has evolved as experience was gained. The authors present a series of 24 patients and a technique that now involves the use of a custom-designed T-plate that is attached to the midline occipital "keel" at one end and to the spine at the other end by means of screw-fixed plates. CONCLUSIONS: Although it is still evolving, the current technique for obtaining rigid occipitocervical fixation allows for immediate rigidity and stability of the spine without the use of an external orthosis (that is, in the absence of osteoporosis), may be extended to any level of the spine, may be used in the absence of posterior elements, prevents postsurgical cranial settling and restenosis, facilitates reduction of the spinal deformity in any plane, and sometimes eliminates the need for an anterior (transoral) decompressive procedure.

Palliative subtotal vertebrectomy with anterior and posterior reconstruction via a single posterior approach.

OBJECT: Laminectomy for the treatment of spinal metastatic disease is ineffective. Total spondylectomy requiring both anterior and posterior operations may cause undue morbidity in patients with a limited life expectancy. The authors demonstrate the technique, feasibility, and success of subtotal vertebrectomy that is followed by anterior and posterior reconstruction via a simple posterior approach. Although this remains a palliative procedure, it provides circumferential decompression and spinal stabilization by using rigid hardware. METHODS: The authors present a review of nine of 43 consecutive patients with spinal metastatic disease who underwent operation in a 42-month period. Via a single midline posterior approach, the authors performed single-stage circumferential decompression of the theca followed by anterior and posterior reconstruction. Anterior support is provided by a methylmethacrylate reconstruction retained with Steinmann pins. Posterior reconstruction is achieved by placement of rigid hook or pedicle screw and rod instrumentation. Eight of the nine patients died of progression of underlying disease. All patients remained pain free until days before they died. Except for a patient with paraplegia who did not recover, all other patients remained ambulatory. Despite radio-, chemo-, and steroid therapy, there were no wound infections or breakdowns. One patient underwent reoperation because of a technical error. CONCLUSIONS: Use of the near-total vertebrectomy followed by anterior and posterior reconstruction from T2 to L3 by using a single midline posterior approach spares the patient, who has a limited life expectancy, the operative risks associated with thoracotomy or thoracoabdominal approaches. The authors restrict the procedure for use in patients with extensive bony disease, noncontiguous spinal involvement, visceral metastases, other contraindications to a transcavitary procedure, and those with advanced age.

Risk factors for adjacent-segment failure following lumbar fixation with rigid instrumentation for degenerative instability.

OBJECT: The authors performed a retrospective analysis of 125 consecutive patients in whom instrumentation was placed to promote lumbar fusion for the treatment of degenerative instability. All procedures were performed by a single surgeon. The authors sought to determine the risk factors for next-segment degeneration after lumbar spinal fusion with rigid instrumentation. METHODS: Thirty-one of 125 fusion procedures were performed in women who were postmenopausal. A total of 18 of 125 patients developed symptomatic next-segment degeneration at a previously asymptomatic level; 15 were postmenopausal women. Data were obtained in patients with next-segment failure based on radiographic studies, neurological assessment, demographic factors, and sequential follow-up examinations. The mean follow-up period for this group was 44.8 months. All women were postmenopausal, and 53% received biphosphonate drugs and calcium supplementation preoperatively for osteopenia. Twenty percent of all patients with next-segment failure were cigarette smokers. Next-segment diseases included spondylolisthesis (39%), spinal canal stenosis due to disc herniation and/or facet hypertrophy (33%), stress fracture of the adjacent vertebral body (28%), and scoliosis (17%). Patients frequently had more than one degenerative process at the next segment. CONCLUSIONS: The risk of adjacent-segment failure is clearly higher for patients in whom lumbar fusion with rigid instrumentation is performed to treat degenerative instability. This risk appears to be especially high in postmenopausal women.

Failure of transodontoid screw fixation. Case report.

Anterior odontoid screw fixation is being performed with increasing frequency and may currently be the treatment of choice for Type II and selected Type III odontoid fractures, because it is the only surgical fusion that preserves C1-2 motion. Typically patients are immobilized postoperatively in a simple cervical collar. The authors present a case of postoperative fracture of the anterior body of the axis secondary to screw dislocation 5 weeks after single anterior odontoid screw osteosynthesis. Possible reasons for this rare complication and its implications for the technique are discussed.

Hyperactivity and hypoactivity in a rat model of Huntington's disease: the systemic 3-nitropropionic acid model.

The present study proposes the use of systemic 3-nitropropionic acid (3-NP) treatment in rats as a model of Huntington's disease (HD). The systemic 3-NP model involves chronic injection of low dose intraperitoneal (i.p.) injections of 3-NP to rats once every 4 days over a period of time. Evidence from our experimental studies suggests that manipulating the number of injections can result in either increased nocturnal spontaneous locomotor activity (hyperactivity) or nocturnal akinesia (hypoactivity) [1]. For example, two injections of 3-NP (using the treatment of one injection every 4 days) result in hyperactivity, while four injections or more of 3-NP lead to hypoactivity [1]. The locomotor activity is recorded by Digiscan locomotor activity monitors [11]. The observation of these two types of locomotor activity is unique since no excitotoxin model has replicated a two-stage progression of a HD-like behavioral alteration. Most studies using excitotoxins like quinolinic acid (QA) and kainic acid (KA) have only reproduced the hyperactivity stage [4,5,7]. With the systemic 3-NP model, investigations into at least two stages of the disease are made possible. This allows for better assessment of intervention strategies such as neural transplants across different stages of the disease. The systemic 3-NP rat model is believed to be an improved animal model of HD.

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.

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.

Cyclosporine-A increases locomotor activity in rats with 6-hydroxydopamine-induced hemiparkinsonism: relevance to neural transplantation.

BACKGROUND: The immunosuppressant cyclosporine-A (CsA) is the primary drug for neural transplantation in Parkinson's disease. However, little is known of its direct effects on movement disorders. Our previous observation of increased locomotor activity in normal rats injected with CsA prompted us to investigate further the effects of CsA on hemiparkinsonian rats. METHODS: We examined the effects of CsA with 6-hydroxydopamine-induced hemiparkinsonism. The animals were randomly assigned to either intraperitoneal injections of CsA (15 mg/kg) or olive oil (the vehicle used for CsA) for 32 days. All animals were tested using the elevated body swing test, and the spontaneous and the amphetamine-induced rotational tests prior to and following the 32-day drug regimen. RESULTS: As revealed by the elevated body swing test, CsA-treated rats had significantly higher mean percent contralateral (to the lesion) swings compared to their pretreatment level (p < 0.01) or to vehicle-treated rats at posttreatment (p < 0.005). In the spontaneous rotational test, CsA-treated rats displayed ipsilateral (to the lesion) rotations which were significantly higher than their pretreatment rotational behavior (p < 0.005) or the posttreatment rotational behavior of olive oil-treated rats (p < 0.0001). Similarly, CsA-treated rats displayed significantly more amphetamine-induced ipsilateral rotations compared to their or the olive oil-treated rats pretreatment level (p < 0.05). CONCLUSION: Our present observations extend our previous findings on motor alterations produced by CsA on normal rats to hemiparkinsonian rats. These results taken together would suggest that CsA may interact with the locomotor effects observed following neural transplantation with adjunctive CsA immunosuppression.

CNS immunological modulation of neural graft rejection and survival.

Neural transplantation therapy as a possible alternative treatment for neurological movement disorders, such as in Parkinson's disease (PD), has accentuated research interest on the immune status of the central nervous system (CNS). Most animal studies concerned with neural transplantation for the treatment of PD have utilized dopamine (DA) neurons from tissues of the embryonic ventral mesencephalon. Rat embryonic DA neurons, grafted either as solid blocks or dissociated into a cell suspension and stereotaxically injected intraparenchymally into a rat lesion model of PD, have been shown to survive and form connections with the host brain, and ameliorate the behavioral deficits of PD. Similarly, studies on nonhuman primate models of PD provide considerable support for neural transplantation of DA neurons as an experimental clinical procedure for the treatment of PD. To this end, experimental clinical trials have been centered upon transplantation of the embryonic ventral mesencephalic cells for PD patients. Although not conclusive, the findings from clinical studies have provided some evidence that most patients with marked increases in fluorodopa uptake (indicating graft survival) have been immunosuppressed. Furthermore, immune reactions have been observed in rats xenografted with human embryonic tissue. Of note, embryonic ventral mesencephalic tissues compared to adult tissues produce better morphological and long-lasting behavioral amelioration of the neurobehavioral deficits of PD, thus advocating the use of grafts from young donors (embryo) to circumvent the CNS immune rejection. The possible graft rejection due to CNS immune reactions, coupled with the social and ethical problems surrounding the use of embryonic neural tissue, and the logistical problems concerning tissue availability have prompted the development of alternative sources of DA-secreting cells. To circumvent these obstacles, several methods have been suggested including the use of immunosuppressants such as Cyclosporine-A, transplantation of autografts, polymer-encapsulated DA-secreting cells, co-culturing and co-transplantation of DA-secreting cells with microcarrier beads, with Sertoli cells, or with fragments of a monoclonal antibody that can mask the MHC class I antigens, and genetically modifying cells that can withstand CNS immune reactions. Some of these techniques allow transplantation of allograft (same species transplantation), or even xenograft (cross species transplantation) without immunosuppression of the recipient. We discuss recent CNS immunosuppression techniques that pose some promise for enhanced survival of neural grafts. When possible, advantages and disadvantages of each method are presented. Hopefully, such critical analysis of different immunosuppression techniques will produce innovated ideas that will lead to a better understanding of CNS immune response and its modulatory function on graft rejection and survival.