The past, present, and future of traumatic spinal cord injury therapies: a review.

This review provides a concise outline of the advances made in the care of patients and to the quality of life after a traumatic spinal cord injury (SCI) over the last century. Despite these improvements reversal of the neurological injury is not yet possible. Instead, current treatment is limited to providing symptomatic relief, avoiding secondary insults and preventing additional sequelae. However, with an ever-advancing technology and deeper understanding of the damaged spinal cord, this appears increasingly conceivable. A brief synopsis of the most prominent challenges facing both clinicians and research scientists in developing functional treatments for a progressively complex injury are presented. Moreover, the multiple mechanisms by which damage propagates many months after the original injury requires a multifaceted approach to ameliorate the human spinal cord. We discuss potential methods to protect the spinal cord from damage, and to manipulate the inherent inhibition of the spinal cord to regeneration and repair. Although acute and chronic SCI share common final pathways resulting in cell death and neurological deficits, the underlying putative mechanisms of chronic SCI and the treatments are not covered in this review.

Lumbar microdiscectomy with intraspine® - a case series / Microdiscectomía lumbar con intraspine® - serie de casos / Microdiscectomia lombar com intraspine® - série de casos

ABSTRACT Objective To assess postoperative outcomes following lumbar microdiscectomy (LMD) with and without the use of a dynamic intralaminar device IntraSPINE ® . Methods A non-randomized single-surgeon retrospective analysis. Consecutive elective surgery was performed on patients with lumbar disc disease over a 16-month period. The study group was determined by electronic theatre database. Ninety-two (62 LMD and 30 ILD) of the 95 eligible patients were included in the study, with three being excluded due to incomplete data sets. The pain scores were assessed pre- and postoperatively using a 4-point scale (0 - pain free; 1 - mild; 2- moderate; 3 - severe). Results The reduction in postoperative leg pain was similar (LMD 1.9 vs. IntraSPINE® 1.8) but the reduction in postoperative back pain was greater in the IntraSPINE® group (LMD 0.5 vs. IntraSPINE® 1.0; p = 0.17). Early recurrence of disc herniation (< 8 months) was lower in the IntraSPINE® group (6.7% vs. 19.4%; p = 0.097). The need for revision surgery was significantly lower in the IntraSPINE® group (p = 0.015). None of the IntraSPINE® recurrences required revision surgery, compared to 97% of the recurrences in the LMD group. Conclusions This case series raises the possibility that in selected patients, the use of the IntraSPINE® may improve back pain and reduce recurrent disc herniation/revision surgery rates in lumbar microdiscectomy. A prospective randomized trial on the use of the IntraSPINE® should be considered, given the clinical and cost implications of revision surgery. Level of Evidence IV; Case series.

RESUMO Objetivo Avaliar os resultados pós-operativos de microdiscectomia lombar (MDL) usando ou não o dispositivo intralaminar dinâmico IntraSPINE®. Métodos Análise retrospectiva simples não randomizada feita por um único cirurgião de cirurgias eletivas consecutivas em pacientes com hérnia de disco lombar no período de 16 meses. O grupo de estudo foi determinado por um banco de dados eletrônicos de centro cirúrgico. Noventa e dois (62 MDL e 30 com dispositivos intralaminares, ILD) dos 95 pacientes elegíveis foram incluídos na pesquisa, sendo que três foram excluídos porque os dados eram incompletos. Os escores de dor foram avaliados no pré e pós-operatório com uma escala de 4 pontos (sendo 0 - sem dor, 1 - leve, 2 - moderada e 3 -severa). Resultados A redução da dor nas pernas no pós-operatório foi similar (MDL 1,9 vs. IntraSPINE® 1,8), mas a redução da dor nas costas no pós-operatório foi melhor no grupo IntraSPINE® (MDL 0,5 vs. IntraSPINE® 1,0; p = 0,17). A reincidência precoce de hérnia de disco (< 8 meses) foi menor no grupo IntraSPINE® (6,7% vs. 19,4%; p = 0,097). A necessidade de cirurgia de revisão foi significativamente menor no grupo IntraSPINE® (p= 0,015). Nenhuma das reincidências no grupo com IntraSPINE® exigiu cirurgia de revisão em comparação com 97% das reincidências do grupo MDL. Conclusões Esta série de casos levanta a possibilidade de que, em pacientes selecionados, o uso de IntraSPINE® pode reduzir a dor nas costas e as taxas de recidiva de hérnia de disco e de cirurgias de revisão na microdiscectomia lombar. Um estudo prospectivo e randomizado do uso do IntraSPINE® deve ser considerado, dadas as implicações clínicas e o custo da cirurgia de revisão. Nível de Evidência IV; Série de casos.

RESUMEN Objetivo Evaluar los resultados postoperatorios de la microdiscectomía lumbar (MDL) utilizando o no el dispositivo intralaminar dinámico IntraSPINE®. Métodos Análisis retrospectivo simple y no aleatorio realizado por uno solo cirujano de cirugías electivas consecutivas en pacientes con hernia de disco lumbar durante un período de 16 meses. El grupo de estudios fue determinado por una base de datos electrónicos de centro quirúrgico. Noventa y dos (62 MDL y 30 con dispositivos intralaminares, ILD) de los 95 elegibles fueron incluidos en el estudio, siendo que tres fueron excluidos porque los datos estaban incompletos. Las puntuaciones de dolor se evaluaron antes y después de la operación con una escala de 4 puntos (0: sin dolor, 1: leve, 2: moderado, 3: grave). Resultados La reducción del dolor postoperatorio de pierna fue similar (MDL 1,9 versus IntraSPINE® 1,8). Sin embargo, la reducción del dolor postoperatorio de la espalda fue mayor en el grupo con IntraSPINE® (MDL 0,5 versus IntraSPINE® 1,0; p = 0,17). La recurrencia temprana de hernia del disco (< 8 meses) fue menor en el grupo IntraSPINE® (6,7% versus 19,4%; p = 0,097). La necesidad de cirugía de revisión fue significativamente menor en el grupo IntraSPINE® (p = 0,015). Ninguna de las recurrencias en el grupo IntraSPINE® requirió cirugía de revisión en comparación con 97% de las recurrencias en el grupo MDL. Conclusiones Esta serie de casos plantea la posibilidad de que, en pacientes seleccionados, el uso de IntraSPINE® pueda reducir el dolor de espalda y reducir las tasas de recurrencia de hernia de disco y las cirugías de revisión en la microdiscectomía lumbar. Se debe considerar un estudio prospectivo y aleatorizado del uso de IntraSPINE®, dadas las implicaciones clínicas y el costo de la cirugía de revisión. Nivel de Evidencia IV; Serie de casos.

Inhibitors of cytochrome c release with therapeutic potential for Huntington's disease.

Release of mitochondrial cytochrome c resulting in downstream activation of cell death pathways has been suggested to play a role in neurologic diseases featuring cell death. However, the specific biologic importance of cytochrome c release has not been demonstrated in Huntington's disease (HD). To evaluate the role of cytochrome c release, we screened a drug library to identify new inhibitors of cytochrome c release from mitochondria. Drugs effective at the level of purified mitochondria were evaluated in a cellular model of HD. As proof of principle, one drug was chosen for in depth evaluation in vitro and a transgenic mouse model of HD. Our findings demonstrate the utility of mitochondrial screening to identify inhibitors of cell death and provide further support for the important functional role of cytochrome c release in HD. Given that many of these compounds have been approved by the Food and Drug Administration for clinical usage and cross the blood-brain barrier, these drugs may lead to trials in patients.

Sequential activation of individual caspases, and of alterations in Bcl-2 proapoptotic signals in a mouse model of Huntington's disease.

Caspases play an important role in neurodegeneration in Huntington's disease (HD). Members of the Bcl-2 family are critical modulators of terminal cell death pathways. However, alterations of Bcl-2 family members and their functional role in an in vivo model of HD have not been documented. With the goal of gaining mechanistic insight, we used a transgenic mouse model of HD (R6/2) to investigate the chronology of caspase activation and functional alterations in members of the Bcl-2 family. In R6/2 mice caspase activation precedes proapoptotic changes in Bcl-2 family members. Of the caspases that we screened, caspase-1-like activation was the first to be detected in the disease process (7 weeks). Proapoptotic changes in members of the Bcl-2 family were first detected at 9 weeks. To demonstrate a potential functional/therapeutic role of Bcl-2 in HD, we crossed R6/2 mice with mice overexpressing Bcl-2 in neurons. Transgenic expression of Bcl-2 in R6/2 mice resulted in slight prolonged survival. Understanding the chronology of apoptotic events provides important information for appropriate therapeutic targeting in this devastating and untreatable disease.

Depletion of wild-type huntingtin in mouse models of neurologic diseases.

Huntington's disease (HD) is caused by a mutation in the gene encoding for huntingtin resulting in selective neuronal degeneration. Because HD is an autosomal dominant disorder, affected individuals have one copy of the mutant and one copy of the wild-type allele. Huntingtin has antiapoptotic properties and is critical for cell survival. However, the important role of wild-type huntingtin in both HD and other neurological diseases has not been fully recognized. We demonstrate disease-associated decreased levels of full-length huntingtin in brains of transgenic mouse models of HD, ischemia, trauma, and in spinal cord after injury. In addition, overexpression of wild-type huntingtin confers in vivo protection of neurodegeneration after ischemia. We propose that in HD, in addition to a toxic gain-of-function of mutant huntingtin, a parallel depletion of wild-type huntingtin results in a detrimental loss-of-function, playing an important role in disease progression.

Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington's disease.

Minocycline is broadly protective in neurologic disease models featuring cell death and is being evaluated in clinical trials. We previously demonstrated that minocycline-mediated protection against caspase-dependent cell death related to its ability to prevent mitochondrial cytochrome c release. These results do not explain whether or how minocycline protects against caspase-independent cell death. Furthermore, there is no information on whether Smac/Diablo or apoptosis-inducing factor might play a role in chronic neurodegeneration. In a striatal cell model of Huntington's disease and in R6/2 mice, we demonstrate the association of cell death/disease progression with the recruitment of mitochondrial caspase-independent (apoptosis-inducing factor) and caspase-dependent (Smac/Diablo and cytochrome c) triggers. We show that minocycline is a drug that directly inhibits both caspase-independent and -dependent mitochondrial cell death pathways. Furthermore, this report demonstrates recruitment of Smac/Diablo and apoptosis-inducing factor in chronic neurodegeneration. Our results further delineate the mechanism by which minocycline mediates its remarkably broad neuroprotective effects.

Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice.

Minocycline mediates neuroprotection in experimental models of neurodegeneration. It inhibits the activity of caspase-1, caspase-3, inducible form of nitric oxide synthetase (iNOS) and p38 mitogen-activated protein kinase (MAPK). Although minocycline does not directly inhibit these enzymes, the effects may result from interference with upstream mechanisms resulting in their secondary activation. Because the above-mentioned factors are important in amyotrophic lateral sclerosis (ALS), we tested minocycline in mice with ALS. Here we report that minocycline delays disease onset and extends survival in ALS mice. Given the broad efficacy of minocycline, understanding its mechanisms of action is of great importance. We find that minocycline inhibits mitochondrial permeability-transition-mediated cytochrome c release. Minocycline-mediated inhibition of cytochrome c release is demonstrated in vivo, in cells, and in isolated mitochondria. Understanding the mechanism of action of minocycline will assist in the development and testing of more powerful and effective analogues. Because of the safety record of minocycline, and its ability to penetrate the blood-brain barrier, this drug may be a novel therapy for ALS.