The Vegetative State And Stem Cells: Therapeutic Considerations

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)The vegetative state (VS), also known as "unresponsive wakefulness syndrome," is considered one of the most devastating outcomes of acquired brain injury. While diagnosis of this condition is generally well-defined clinically, patients often appear to be awake despite an absence of behavioral signs of awareness, which to the family can be confusing, leading them to believe the loved one is aware of their surroundings. This inequality of agreement can be very distressing. Currently, no cure for the VS is available; as a result, patients may remain in this condition for the rest of their lives, which in some cases amount to decades. Recent advances in stem cell approaches for the treatment of other neurological conditions may now provide an opportunity to intervene in this syndrome. This mini review will address the development of VS, its diagnosis, affected cerebral structures, and the underlying basis of how stem cells can offer therapeutic promise that would take advantage of the often long-term features associated with this maladie to effect a repair of the severely damaged circuitry. In addition, current limitations of this treatment strategy, including a lack of animal models, few long-term clinical studies that might identify benefits of stem cell treatment, and the potential for development of tumors are considered.7Canadian Institutes of Health ResearchFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) in BrazilFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

MODELS OF EPILEPSY USED IN ANTIEPILEPTIC DRUG DISCOVERY: A REVIEW

This article describes various experimental models of seizure and epilepsy. Epilepsy is characterised by recurrent unprovoked seizures. Antiepileptic drug discovery in animal models starts with the assumption that the experimental seizure model mimics human seizure. Hence a drug which suppresses ictogenesis or inhibits epileptogenesis in animal model is a potential antiepileptic drug for human and it needs further investigation. Phenytoin and Carbamazepine were identified with the help of relatively simple models like Maximal electroshock seizure and the pentylenetetrazole test. Lots of drugs were discovered with the help of these models but a big portion of patients still remains resistant to the available antiepileptic drugs. Again these simple seizure models are increasingly being questioned, are they providing us same type of drugs with same kind of mechanism of action? This question brings the importance of newer animal models that target epileptogenesis, pharmacoresistant epilepsy and models which mimic human epilepsy more closely. There is increased concern on agents for epilepsy disease modification and prevention. To solve these unmet needs, the research scientist must have a thorough knowledge of available animal models of epilepsy so that he can pick up the best model for his research. In this article, we are reviewing the diversity of animal models of epilepsy and their implications in antiepileptic drug discovery

Melanocortins and the cholinergic anti-inflammatory pathway.

Experimental evidence indicates that small concentrations of inflammatory molecules produced by damaged tissues activate afferent signals through ascending vagus nerve fibers, that act as the sensory arm of an "inflammatory reflex". The subsequent activation of vagal efferent fibers, which represent the motor arm of the inflammatory reflex, rapidly leads to acetylcholine release in organs of the reticuloendothelial system. Acetylcholine interacts with α7 subunit-containing nicotinic receptors in tissue macrophages and other immune cells and rapidly inhibits the synthesis/release of tumor necrosis factor-α and other inflammatory cytokines. This neural anti-inflammatory response called "cholinergic anti-inflammatory pathway" is fast and integrated through the central nervous system. Preclinical studies are in progress, with the aim to develop therapeutic agents able to activate the cholinergic anti-inflammatory pathway. Melanocortin peptides bearing the adrenocorticotropin/α-melanocyte-stimulating hormone sequences exert a protective and life-saving effect in animals and humans in conditions of circulatory shock. These neuropeptides are likewise protective in other severe hypoxic conditions, such as prolonged respiratory arrest, myocardial ischemia, renal ischemia and ischemic stroke, as well as in experimental heart transplantation. Moreover, experimental evidence indicates that melanocortins reverse circulatory shock, prevent myocardial ischemia/reperfusion damage and exert neuroprotection against ischemic stroke through activation of the cholinergic anti-inflammatory pathway. This action occurs via stimulation of brain melanocortin MC3/MC4 receptors. Investigations that determine the molecular mechanisms of the cholinergic anti-inflammatory pathway activation could help design of superselective activators of this pathway

НЕЙРОПРОТЕКТИВНАЯ РОЛЬ ОСНОВНОГО ФАКТОРА РОСТА ФИБРОБЛАСТОВ BFGF ПРИ ИШЕМИЧЕСКОМ ПОВРЕЖДЕНИИ ГОЛОВНОГО МОЗГА (ОБЗОР)

The review deals with basic fibroblast growth factor (bFGF), one of the most known representatives of the family of neutrotrophic factors. It discusses its function in the central nervous system in health and disease, some mechanisms of neuroprotective action, the therapeutic potential of bFGF for the treatment of functional and structural disorders of the nervous system in brain ischemia of different etiologies, and in neurodegenerative diseases. Alternative routes for delivery of this protein to injured cerebral regions are considered.Обзор посвящен одному из наиболее известных представителей семейства нейротрофических факторов – основному фактору роста фибробластов bFGF. Обсуждаются его функции в ЦНС в норме и при патологическом воздействии, некоторые механизмы нейропротективного действия, терапевтический потенциал bFGF для лечения функциональных и структурных нарушений нервной системы при ишемии головного мозга различной этиологии, а также при нейродегенеративных заболеваниях. Рассмотрены альтернативные способы доставки этого белка к поврежденным областям головного мозга

The role of Insulin-like Growth Factors (IGFs) and IGF-binding proteins in the nervous system

The insulin-like growth factors (IGF-I and IGF-II) and their receptors are widely expressed in nervous tissue from early embryonic life. They also cross the blood brain barriers by active transport, and their regulation as endocrine factors therefore differs from other tissues. In brain, IGFs have paracrine and autocrine actions that are modulated by IGF-binding proteins and interact with other growth factor signalling pathways. The IGF system has roles in nervous system development and maintenance. There is substantial evidence for a specific role for this system in some neurodegenerative diseases, and neuroprotective actions make this system an attractive target for new therapeutic approaches. In developing new therapies, interaction with IGF-binding proteins and other growth factor signalling pathways should be considered. This evidence is reviewed, gaps in knowledge are highlighted, and recommendations are made for future research

The link between iron, metabolic syndrome, and Alzheimer's disease

Both Alzheimer's disease (AD), the most common form of dementia, and type-2 diabetes mellitus (T2DM), a disease associated with metabolic syndrome (MetS), affect a great number of the world population and both have increased prevalence with age. Recently, many studies demonstrated that pre-diabetes, MetS, and T2DM are risk factors in the development of AD and have many common mechanisms. The main focus of studies is the insulin resistance outcome found both in MetS as well as in brains of AD subjects. However, oxidative stress (OS)-related mechanisms, which are well known to be involved in AD, including mitochondrial dysfunction, elevated iron concentration, reactive oxygen species (ROS), and stress-related enzyme or proteins (e.g. heme oxygenase-1, transferrin, etc.), have not been elucidated in MetS or T2DM brains although OS and iron are involved in the degeneration of the pancreatic islet β cells. Therefore, this review sets to cover the current literature regarding OS and iron in MetS and T2DM and the similarities to mechanisms in AD both in human subjects as well as in animal model

Pharmacological Neuroprotection after Perinatal Hypoxic-Ischemic Brain Injury

Perinatal hypoxia-ischemia (HI) is an important cause of neonatal brain injury. Recent progress in the search for neuroprotective compounds has provided us with several promising drugs to reduce perinatal HI-induced brain injury. In the early stage (first 6 hours after birth) therapies are concentrated on prevention of the production of reactive oxygen species or free radicals (xanthine-oxidase-, nitric oxide synthase-, and prostaglandin inhibition), anti-inflammatory effects (erythropoietin, melatonin, Xenon) and anti-apoptotic interventions (nuclear factor kappa B- and c-jun N-terminal kinase inhibition); in a later stage stimulation of neurotrophic properties in the neonatal brain (erythropoietin, growth factors) can be targeted to promote neuronal and oligodendrocyte regeneration. Combination of pharmacological means of treatment with moderate hypothermia, which is accepted now as a meaningful therapy, is probably the next step in clinical treatment to fight post-asphyxial brain damage. Further studies should be directed at a more rational use of therapies by determining the optimal time and dose to inhibit the different potentially destructive molecular pathways or to enhance endogenous repair while at the same time avoiding adverse effects of the drugs used