Evidence and implications for early intervention in bipolar disorder

Aims: To review the evidence that supports early intervention in the treatment of bipolar disorder.

Background: Bipolar disorder is a pleomorphic condition, with varying manifestations that are determined by a number of complex factors including the ‘‘stage’’ of illness. It is consequently a notoriously difficult illness to diagnose and as a corollary is associated with lengthy delays in recognition and the initiation of suitable treatment.

Methods: A literature search was conducted using MEDLINE augmented by a manual search.

Results: Emerging neuroimaging data suggests that, in contrast to schizophrenia, where at the time of a first-episode of illness there is already discernible volume loss, in bipolar disorder, gross brain structure is relatively preserved, and it is only with recurrences that there is a sequential, but marked loss of brain volume. Recent evidence suggests that both pharmacotherapy and psychotherapy are more effective if instituted early in the course of bipolar disorder, and that with multiple episodes and disease progression there is a noticeable decline in treatment response.

Conclusions: Such data supports the notion of clinical staging, and the tailored implementation of treatments according to the stage of illness. The progressive nature of bipolar disorder further supports the concept that the first episode is a period that requires energetic broad-based treatment, with the hope that this could alter the temporal trajectory of the illness. It also raises hope that prompt treatment may be neuroprotective and that this perhaps attenuates or even prevents the neurostructural and neurocognitive changes seen to emerge with chronicity. This highlights the need for early identification at a population level and the necessity of implementing treatments and services at a stage of the illness where prognosis is optimal.

Early intervention in bipolar disorders : clinical, biochemical and neuroimaging imperatives

In the absence of clear targets for primary prevention of many psychiatric illnesses, secondary prevention becomes the most feasible therapeutic target, and is best encompassed by the concept of early intervention. This construct encompasses the goals of minimising diagnostic delay and the prompt initiation of clinically appropriate therapy. This paper develops the rationale for early intervention in bipolar disorder. Three interrelated themes are discussed; the clinical data supporting the value of prompt diagnosis and treatment in bipolar disorder, the putative biochemical mechanisms underlying the pathophysiological processes, and the parallel concept of neuroprotection, and the developing neuroimaging data that supports early intervention. Early initiation of appropriate therapy may potentially facilitate improved clinical outcomes, and further might allow the secondary prevention of the sequelae of untreated illness, which include the deleterious impact on family relationships, psychosexual and vocational development, identity and self-concept and self-stigma.

Using lithium as a neuroprotective agent in patients with cancer

Neurocognitive impairment is being increasingly recognized as an important issue in patients with cancer who develop cognitive difficulties either as part of direct or indirect involvement of the nervous system or as a consequence of either chemotherapy-related or radiotherapy-related complications. Brain radiotherapy in particular can lead to significant cognitive defects. Neurocognitive decline adversely affects quality of life, meaningful employment, and even simple daily activities. Neuroprotection may be a viable and realistic goal in preventing neurocognitive sequelae in these patients, especially in the setting of cranial irradiation. Lithium is an agent that has been in use for psychiatric disorders for decades, but recently there has been emerging evidence that it can have a neuroprotective effect.

This review discusses neurocognitive impairment in patients with cancer and the potential for investigating the use of lithium as a neuroprotectant in such patients.

The science and practice of lithium therapy

Introduction: Despite more that 60 years of clinical experience, the effective use of lithium for the treatment of mood disorder, in particular bipolarity, is in danger of becoming obsolete. In part, this is because of exaggerated fears surrounding lithium toxicity, acute and long-term tolerability and the encumbrance of life-long plasma monitoring. Recent research has once again positioned lithium centre stage and amplified the importance of understanding its science and how this translates to clinical practice.

Objective: The aim of this paper is to provide a sound knowledge base as regards the science and practice of lithium therapy.

Method: A comprehensive literature search using electronic databases was conducted along with a detailed review of articles known to the authors pertaining to the use of lithium. Studies were limited to English publications and those dealing with the management of psychiatric disorders in humans. The literature was synthesized and organized according to relevance to clinical practice and understanding.

Results: Lithium has simple pharmacokinetics that require regular dosing and monitoring. Its mechanisms of action are complex and its effects are multi-faceted, extending beyond mood stability to neuroprotective and anti-suicidal properties. Its use in bipolar disorder is under-appreciated, particularly as it has the best evidence for prophylaxis, qualifying it perhaps as the only true mood stabilizer currently available. In practice, its risks and tolerability are exaggerated and can be readily minimized with knowledge of its clinical profile and judicious application.

Conclusion: Lithium is a safe and effective agent that should, whenever indicated, be used first-line for the treatment of bipolar disorder. A better understanding of its science alongside strategic management of its plasma levels will ensure both wider utility and improved outcomes.

Human neuronal cells : epigenetic aspects

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) promote histone posttranslational modifications, which lead to an epigenetic alteration in gene expression. Aberrant regulation of HATs and HDACs in neuronal cells results in pathological consequences such as neurodegeneration. Alzheimer's disease is the most common neurodegenerative disease of the brain, which has devastating effects on patients and loved ones. The use of pan-HDAC inhibitors has shown great therapeutic promise in ameliorating neurodegenerative ailments. Recent evidence has emerged suggesting that certain deacetylases mediate neurotoxicity, whereas others provide neuroprotection. Therefore, the inhibition of certain isoforms to alleviate neurodegenerative manifestations has now become the focus of studies. In this review, we aimed to discuss and summarize some of the most recent and promising findings of HAT and HDAC functions in neurodegenerative diseases.

Engineering a multimodal nerve conduit for repair of injured peripheral nerve

Injury to nerve tissue in the peripheral nervous system (PNS) results in long-term impairment of limb function, dysaesthesia and pain, often with associated psychological effects. Whilst minor injuries can be left to regenerate without intervention and short gaps up to 2 cm can be sutured, larger or more severe injuries commonly require autogenous nerve grafts harvested from elsewhere in the body (usually sensory nerves). Functional recovery is often suboptimal and associated with loss of sensation from the tissue innervated by the harvested nerve. The challenges that persist with nerve repair have resulted in development of nerve guides or conduits from non-neural biological tissues and various polymers to improve the prognosis for the repair of damaged nerves in the PNS. This study describes the design and fabrication of a multimodal controlled pore size nerve regeneration conduit using polylactic acid (PLA) and (PLA):poly(lactic-co-glycolic) acid (PLGA) fibers within a neurotrophin-enriched alginate hydrogel. The nerve repair conduit design consists of two types of PLGA fibers selected specifically for promotion of axonal outgrowth and Schwann cell growth (75:25 for axons; 85:15 for Schwann cells). These aligned fibers are contained within the lumen of a knitted PLA sheath coated with electrospun PLA nanofibers to control pore size. The PLGA guidance fibers within the nerve repair conduit lumen are supported within an alginate hydrogel impregnated with neurotrophic factors (NT-3 or BDNF with LIF, SMDF and MGF-1) to provide neuroprotection, stimulation of axonal growth and Schwann cell migration. The conduit was used to promote repair of transected sciatic nerve in rats over a period of 4 weeks. Over this period, it was observed that over-grooming and self-mutilation (autotomy) of the limb implanted with the conduit was significantly reduced in rats implanted with the full-configuration conduit compared to rats implanted with conduits containing only an alginate hydrogel. This indicates return of some feeling to the limb via the fully-configured conduit. Immunohistochemical analysis of the implanted conduits removed from the rats after the four-week implantation period confirmed the presence of myelinated axons within the conduit and distal to the site of implantation, further supporting that the conduit promoted nerve repair over this period of time. This study describes the design considerations and fabrication of a novel multicomponent, multimodal bio-engineered synthetic conduit for peripheral nerve repair.

The potential utility of a staging model as a course specifier: a bipolar disorder perspective.

Staging models are widely used in clinical medicine, and offer an insight into the progressive nature of many disorders. In general, the earlier stages of illness may be associated with a better prognosis and a higher treatment response. Once chronicity is reached, more complex and invasive treatments may be required, and the utility of treatments may decline. There is evidence that treatment response is greatest in the early phases of the disorder. There is also a progressive social and psychological burden of ongoing illness. This is paralleled by the twin notions of neuroprotection, which is supported by increasing evidence that structural changes in the disorder may be progressive and reversible with algorithm appropriate treatment, and that of early intervention, which posits that the optimal window for intervention is early in the illness course. A staging model compliments existing and proposed classifications of bipolar disorder, adding a temporal dimension to a cross sectional view. It may inform treatment choice and prognosis, and could have utility as a course specifier.

Electrophysiological effects of guanosine and MK-801 in a quinolinic acid-induced seizure model

TORRES, F ; FILHO, M.S. ; ANTUNES, C. ; KALININE, E. ; ANTONIOLLI, E. ; PORTELA, Luis Valmor ; SOUZA, Diogo Onofre ; TORT, A. B. L. . Electrophysiological effects of guanosine and MK-801 in a quinolinic acid-induced seizure model. Experimental Neurology , v. 221, p. 296-306, 2010

Síndrome glaucomatosa em cães: parte 2

O glaucoma mantém-se como uma das principais causas de cegueira em pacientes humanos e entre os animais domésticos. No curso da sua patogênese, ocorre aumento da pressão intra-ocular e morte de células retinianas, cujo início pode ser precoce. Fármacos vêm sendo desenvolvidos visando a se obter o controle da pressão intra-ocular e a proteger as células retinianas da apoptose e morte. O presente artigo revisa a farmacologia, as indicações e os efeitos adversos das principais substâncias utilizadas topicamente no tratamento do glaucoma em cães, além de discutir as técnicas cirúrgicas contemporâneas que passam melhor se adequar ao seu controle.

Advances in drug design based on the amino acid approach: Taurine analogues for the treatment of CNS diseases

Amino acids are well known to be an important class of compounds for the maintenance of body homeostasis and their deficit, even for the polar neuroactive aminoacids, can be controlled by supplementation. However, for the amino acid taurine (2-aminoethanesulfonic acid) this is not true. Due its special physicochemical properties, taurine is unable to cross the blood-brain barrier. In addition of injured taurine transport systems under pathological conditions, CNS supplementation of taurine is almost null. Taurine is a potent antioxidant and anti-inflammatory semi-essential amino acid extensively involved in neurological activities, acting as neurotrophic factor, binding to GABA A/glycine receptors and blocking the excitotoxicity glutamate-induced pathway leading to be a neuroprotective effect and neuromodulation. Taurine deficits have been implicated in several CNS diseases, such as Alzheimer's, Parkinson's, epilepsy and in the damage of retinal neurons. This review describes the CNS physiological functions of taurine and the development of new derivatives based on its structure useful in CNS disease treatment.&; 2012 by the authors; licensee MDPI, Basel, Switzerland.

Motor Recovery and Synaptic Preservation after Ventral Root Avulsion and Repair with a Fibrin Sealant Derived from Snake Venom

Background:Ventral root avulsion is an experimental model of proximal axonal injury at the central/peripheral nervous system interface that results in paralysis and poor clinical outcome after restorative surgery. Root reimplantation may decrease neuronal degeneration in such cases. We describe the use of a snake venom-derived fibrin sealant during surgical reconnection of avulsed roots at the spinal cord surface. The present work investigates the effects of this fibrin sealant on functional recovery, neuronal survival, synaptic plasticity, and glial reaction in the spinal motoneuron microenvironment after ventral root reimplantation.Methodology/Principal Findings:Female Lewis rats (7 weeks old) were subjected to VRA and root replantation. The animals were divided into two groups: 1) avulsion only and 2) replanted roots with fibrin sealant derived from snake venom. Post-surgical motor performance was evaluated using the CatWalk system twice a week for 12 weeks. The rats were sacrificed 12 weeks after surgery, and their lumbar intumescences were processed for motoneuron counting and immunohistochemistry (GFAP, Iba-1 and synaptophysin antisera). Array based qRT-PCR was used to evaluate gene regulation of several neurotrophic factors and receptors as well as inflammatory related molecules. The results indicated that the root reimplantation with fibrin sealant enhanced motor recovery, preserved the synaptic covering of the motoneurons and improved neuronal survival. The replanted group did not show significant changes in microglial response compared to VRA-only. However, the astroglial reaction was significantly reduced in this group.Conclusions/Significance:In conclusion, the present data suggest that the repair of avulsed roots with snake venom fibrin glue at the exact point of detachment results in neuroprotection and preservation of the synaptic network at the microenvironment of the lesioned motoneurons. Also such procedure reduced the astroglial reaction and increased mRNA levels to neurotrophins and anti-inflammatory cytokines that may in turn, contribute to improving recovery of motor function. © 2013 Barbizan et al.

Estudo da relação estrutura/atividade para as ações neurotóxica/neuroprotetora das acilpoliaminotoxinas NSTX-3 e JSTX-3 em sistema nervoso central de ratos

Pós-graduação em Ciências Biológicas (Biologia Celular e Molecular) - IBRC

Tratamento com minociclina e transplante intraestriatal de células mononucleares da medula óssea após acidente vascular experimental encefálico

Diversos estudos sugerem que a tetraciciclina semi-sintética minociciclina e o transplante de células mononucleares da medula óssea (CMMOs) induzem neuroproteção em modelos experimentais de acidente vascular encefálico (AVENC). No entanto, poucos investigaram, comparativamente, os efeitos destas duas abordagens terapêuticas após AVENC induzido por microinjeções de endotelina – 1 (ET -1). Nesta dissertação, objetivou-se comparar os efeitos do bloqueio microglial com minociclina com os obtidos pelo transplante intraestriatal de CMMOs na fase aguda após acidente vascular encefálico experimental, sobre a área de lesão, neuroproteção, apoptose de recuperação funcional. Ratos machos adultos, da raça Wistar, pesando entre 250 e 350g, foram distribuídos em quatro grupos experimentais: controle (chamado de Salina) - isquêmico tratado com salina (N=4), isquêmico tratado com minociclina (N=4), isquêmico tratado com CMMOs (N=3) e doador de CMMOs (N=2). Testes comportamentais foram realizados em 1, 3 e 7 dias pós-isquemia para avaliar a recuperação funcional entre os grupos. Animais tratados com minociclina receberam 2 doses diárias de 50mg/kg nos 2 primeiros dias, e 5 aplicações únicas de 25mg/kg (i.p) nos dias subsequentes até o sexto dia após a indução isquêmica. 1x106 de CMMOs foram obtidas de ratos da mesma linhagem e transplantadas diretamente no estriato, 24h após a lesão isquêmica. Todos os animais foram perfundidos 7 dias após a indução isquêmica. Secções coronais foram coradas por violeta de cresila para análise histopatológica geral, e por imunohistoquímica para a identificação de corpos neuronais (neuN), microglia/macrófagos ativados (ED1) e células apoptóticas (Caspase-3). A análise histopatológica geral mostrou grande palor, perda tecidual e intensa ativação microglial/ macrofágica no estriato de animais tratados com solução salina estéril. O tratamento com CMMO foi mais eficaz do que a minociclina (P<0,05, ANOVA-Tukey) na redução do número de microglia/macrófagos ativados (salina 276,3 ± 9,3); CMMOs 133,8 ± 6,8) e minociclina 244,6 ± 7,1). CMMOs e minociclina reduziram a área de lesão, em 67,75% e 69,1%, respectivamente. Os dois tratamentos promoveram o mesmo nível de preservação neuronal (p< 0,05) em relação ao controle, 61,3 ± 1,5); 86,8 ± 3,4) e 81 ± 3,4). As CMMOs reduziram de forma mais eficaz (p<0,01) o número de células apoptóticas em relação à minociclina e grupo controle (26,5 ± 1,6); 13,1 ± 0,7) e 19,7 ± 1,1). Ambas as abordagens terapêuticas promoveram recuperação funcional dos animais isquêmicos. Os resultados sugerem que o tratamento com CMMOs é mais eficaz na modulação da resposta microglial e na diminuição da apoptose do que o tratamento com minociclina, apesar de ambos serem igualmente eficazes para indução da neuroproteção. Estudos futuros devem investigar se o tratamento com minociclina associado ao transplante de CMMOs produzem efeitos sinérgicos, o que poderia amplificar os níveis de neuroproteção observados.