The hypothalamus may be involved in regulating homeostasis, motivation, and emotional behavior by
controlling autonomic and endocrine activity. The hypothalamus communicates input from the thalamus to the pituitary
gland, reticular activating substance, limbic system, and neocortex. This allows the output of pituitary hormones to
respond to changes in autonomic nervous system activity. Environmental heat stress increases cutaneous blood flow and
metabolism, and progressively decreases splanchnic blood flow. Severe heat exposure also decreases mean arterial
pressure (MAP), increases intracranial pressure (ICP), and decreases cerebral perfusion pressure (CPP = MAP – ICP), all
of which lead to cerebral ischemia and hypoxia. Compared with normothermic controls, rodents with heatstroke have
higher hypothalamic values of cellular ischemia (e.g., glutamate and lactate-to-pyruvate ratio) and damage (e.g., glycerol)
markers, pro-oxidant enzymes (e.g., lipid peroxidation and glutathione oxidation), proinflammatory cytokines (e.g.,
interleukin-1β and tumor necrosis factor-α), inducible nitric oxide synthase-dependent nitric oxide, and an indicator for
the accumulation of polymorphonuclear leukocytes (e.g., myeloperoxidase activity), as well as neuronal damage (e.g.,
apoptosis, necrosis, and autophagy) after heatstroke. Hypothalamic values of antioxidant defenses (e.g., glutathione
peroxidase and glutathione reductase), however, are lower. The ischemic, hypoxic, and oxidative damage to the
hypothalamus during heatstroke may cause multiple organ dysfunction or failure through hypothalamic-pituitary-adrenal
axis mechanisms. Finding the link between the signaling and heatstroke-induced hypothalamic oxidative and ischemic
damage might allow us to clinically attenuate heatstroke. In particular, free radical scavengers, heat shock protein-70
inducers, hypervolemic hemodilution, inducible nitric oxide synthase inhibitors, progenitor stem cells, flutamide,
estrogen, interleukin-1 receptor antagonists, glucocorticoid, activated protein C, and baicalin mitigate preclinical
Hypothalamus; heatstroke; hypotension; ischemia; hypoxia; oxidative stress; cytokines; inflammation; antioxidants; pharmacology.
The bed nucleus of the stria terminalis (BNST) is a heterogeneous and complex limbic forebrain structure, which plays an important role in controlling autonomic, neuroendocrine and behavioral responses. The BNST is thought to serve as a key relay connecting limbic forebrain structures to hypothalamic and brainstem regions associated with autonomic and neuroendocrine functions. Its control of physiological and behavioral activity is mediated by local action of numerous neurotransmitters. In the present review we discuss the role of the BNST in control of both autonomic and neuroendocrine function. A description of BNST control of cardiovascular and hypothalamus-pituitary-adrenal axisactivity at rest and during physiological challenges (stress and physical exercise) is presented. Moreover, evidence for modulation of hypothalamic magnocellular neurons activity is also discussed. We attempt to focus on the discussion of BNST neurochemical mechanisms. Therefore, the source and targets of neurochemical inputs to BNST subregions and their role in control of autonomic and neuroendocrine function is discussed in details.
BNST; cardiovascular function; extended amygdala; neurotransmitters; HPA axis; vasopressin; stress and physical exercise.
Data from many experiments has shown that serotonin2C (5-HT2C) receptor plays a role in the control of orofacial activity in rodents. Purposeless oral movements can be elicited either by agonists or inverse agonists implying a tight control exerted by the receptor upon oral activity. The effects of agonists has been related to an action of these drugs in the subthalamic nucleus and the striatum, the two input structures for cortical efferents to the basal ganglia, a group of subcortical structures involved in the control of motor behaviors. The oral effects of agonists are dramatically enhanced in case of chronic blockade of central dopaminergic transmission induced by neuroleptics or massive destruction of dopamine neurons. The mechanisms involved in the hypersensitized oral responses to 5-HT2C agonists are not clear and deserve additional studies. Indeed, while the oral behavior triggered by 5-HT2C drugs would barely correspond to the dyskinesia observed in humans, the clinical data have consistently postulated that 5-HT2C receptors could be involved in these aberrant motor manifestations.
Serotonin2c receptor; oral activity; neuroleptic; 6-hydroxydopamine lesion; hypersensitized oral responses.
Neuropsychiatric disorders are devastating mental illnesses with a high economic burden. The additional morbidity associated with social issues that arises along with the course of these diseases increases the need for a clear understanding of their etiopathogenesis to allow an implementation of novel pharmacological strategies. Yet a poor knowledge about interactions occurring at the glia-neuron interface in health and disease still hampers innovative discoveries, despite the fact that glia cells have been long described to actively participate in the regulation of brain circuits.
The purpose of this review was to collect the scattered literature on the involvement of glia cells in neuropsychiatric disorders and to describe how also these cells besides neurons might be responsive to current pharmacological interventions. We hope thereby to offer alternative approaches for investigations that may open avenues to search for new potential targets for drug discovery.
Astrocytes; microglia; neuropsychiatric disorders; oligodendrocytes; pharmacotherapy
Since attention deficit/hyperactivity disorder (ADHD) presents high prevalence among children, science has been researching alternative forms of treatment that do not involve medication. Objective: To evaluate the effects of polyunsaturated fatty acids (PUFAs) on attention deficit/hyperactivity disorder. Methods: We reviewed the articles published between 1980 and 2012 indexed in the databases PubMed, APA psychNET, Scopus and Web of Knowledge. Results: Initially 231 articles were selected, out of which 12 met the inclusion criteria. The articles selected reported a modest cognitive and behavioral improvement of the patients after treatment with low doses of PUFAs. Those results might be associated with the evaluation methodology, the doses of PUFAs administered or the duration of treatment.
Attention deficit/hyperactivity disorder; behavior; children; cognition; dietary supplements and polyunsaturated fatty acids.
The blood-brain barrier (BBB), a dynamic and complex barrier formed by endothelial cells, can impede the entry of unwanted substances – pathogens and therapeutic molecules alike – into the central nervous system (CNS) from the blood circulation. Taking into account the fact that CNS-related diseases are the largest and fastest growing unmet medical concern, many potential protein- and nucleic acid-based medicines have been developed for therapeutic purposes. However, due to their poor ability to cross the BBB and the plasma membrane, the above-mentioned bio-macromolecules have limited use in treating neurological diseases. Finding effective, safe, and convenient ways to deliver therapeutic molecules into the CNS is thus urgently required. In recent decades, much effort has been expended in the development of drug delivery technologies, of which cell-penetrating peptides (CPPs) have the most promising potential. The present review covers the latest advances in CPP delivery technology, and provides an update on their use in CNS-targeted drug delivery.
Central nervous system; blood-brain barrier; cell-penetrating peptides; drug delivery.
The renin-angiotensin system (RAS) in brain is a crucial regulator for physiological homeostasis and diseases of cerebrovascular system, such as ischemic stroke. Overactivation of brain Angiotensin-converting enzyme (ACE) - Angiotensin II (Ang II) - Angiotensin II type 1 receptor (AT1R) axis was found to be involved in the progress of hypertension, atherosclerosis and thrombogenesis, which increased the susceptibility to ischemic stroke. Besides, brain Ang II levels have been revealed to be increased in ischemic tissues after stroke, and contribute to neural damage through elevating oxidative stress levels and inducing inflammatory response in the ischemic hemisphere via AT1R. In recent years, new components of RAS have been discovered, including ACE2, Angiotensin-(1–7) [Ang-(1-7)] and Mas, which constitute ACE2-Ang-(1-7)-Mas axis. ACE2 converts Ang II to Ang-(1-7), and Ang-(1-7) binds with its receptor Mas, exerting benefical effects in cerebrovascular disease. Through interacting with nitric oxide and bradykinin, Ang-(1-7) could attenuate the development of hypertension and the pathologic progress of atherosclerosis. Besides, its antithrombotic activity also prevents thrombogenic events, which may contribute to reduce the risk of ischemic stroke. In addition, after ischemia insult, ACE2-Ang-(1-7)-Mas has been shown to reduce the cerebral infarct size and improve neurological deficits through its antioxidative and anti-inflammatory effects. Taken together, activation of the ACE2-Ang-(1-7)-Mas axis may become a novel therapeutic target in prevention and treatment of ischemia stroke, which deserves further investigations.
Renin-angiotensin system; Angiotensin-(1-7); Stroke; Neuroprotection; Oxidative stress.
Vasopressin (VP) and oxytocin (OT) are mainly synthesized in the magnocellular neurons of the paraventricular (PVN) and supraoptic nucleus (SON) of the hypothalamus. Axons from the magnocellular part of the PVN and SON project to neurohypophysis where VP and OT are released in blood to act like hormones. Axons from the parvocellular part of PVN project to extra-hypothalamic brain areas (median eminence, limbic system, brainstem and spinal cord) where VP and OT act like neurotransmitters/modulators. VP and OT act in complementary manner in cardiovascular control, both as hormones and neurotransmitters. While VP conserves water and increases circulating blood volume, OT eliminates sodium. Hyperactivity of VP neurons and quiescence of OT neurons in PVN underlie osmotic adjustment to pregnancy. In most vascular beds VP is a potent vasoconstrictor, more potent than OT, except in the umbilical artery at term. The vasoconstriction by VP and OT is mediated via V1aR. In some vascular beds, i.e. the lungs and the brain, VP and OT produce NO dependent vasodilatation. Peripherally, VP has been found to enhance the sensitivity of the baro-receptor while centrally, VP and OT increase sympathetic outflow, suppresse baro-receptor reflex and enhance respiration. Whilst VP is an important mediator of stress that triggers ACTH release, OT exhibits anti-stress properties. Moreover, VP has been found to contribute considerably to progression of hypertension and heart failure while OT has been found to decrease blood pressure and promote cardiac healing.
Vasopressin; oxytocin; respiration; blood pressure; baro-receptor reflex; stress; hypertension; heart failure.
Mild cognitive impairment (MCI) is a syndrome which, depending on various neurobiological, psychological and social factors, carries a high risk of developing into dementia. As far as diagnostic uncertainty and the heterogeneous underlying pathophysiological mechanisms are concerned, only limited therapeutic options are currently available. Clinical trials involving a wide range of substances have failed to show efficacy on primary and secondary outcome parameters. Most results reflect not only a lack of effectiveness of drug therapy but also methodological constraints in true prodromal Alzheimer´s disease (AD) based on clinical criteria. Biomarkers may help to identify MCI as a prodromal phase of dementia, so it is important to use them to improve specificity of case selection in future studies. For MCI as a prodromal syndrome of AD, clinical trials with disease modifying drugs that target underlying pathological mechanisms such as amyloid-beta accumulation and neurofibrillary tangle formation may help develop effective treatment options in the future. Alternative pharmacological approaches are currently being evaluated in ongoing phase 1 and phase 2 studies. Nevertheless, a lack of approved pharmacotherapeutic options has led to specific interventions that focus on patient education and life-style related factors receiving increasing attention.
Mild cognitive impairment; Alzheimer’s Dementia; Clinical Trials; Treatment.
The neurobiological etiopathogenesis of OCD is still obscure. Neuroimaging studies have been very influential in shaping neurobiological models of OCD. Investigations performed within last twenty years have revealed some important findings and proposed that specific cortico-striato-thalamic circuits are involved in the mediation of its symptoms. The effects of antiobsessional drugs and cognitive behavioral therapy on structural and functional imaging have been evaluated in limited size of investigations. In structural investigations, in summary, it was found key brain regions in the pathophysiology of OCD and amygdala to change volumetrically by treatment. In functional and neurochemical investigations, by using different treatment modalities, cortico-striatal function disablements and NAA changes in a variety of brain regions were reported. In this paper, these limited data are reviewed. It is clear that there is so many things to be performed in the future researches on the effects of therapy on brains of the patients with OCD.
OCD; Structurel; MRI; MRS; fMRI.
Until recently, epilepsy medical therapy is usually limited to anti-epileptic drugs (AEDs). However, approximately 1/3 of epilepsy patients, described as drug-resistant epilepsy (DRE) patients, still suffer from continuous frequent seizures despite receiving adequate AEDs treatment of sufficient duration. More recently, with the remarkable progress of immunology, immunity and inflammation are considered to be key elements of the pathobiology of epilepsy. Activation of inflammatory processes in brain tissue has been observed in both experimental seizure animal models and epilepsy patients. Anti-inflammatory and immunotherapies also showed significant anticonvulsant properties both in clinical and in experimental settings. The above emerging evidence indicates that modulation of immunity and inflammatory processes could serve as novel specific targets to achieve potential anticonvulsant effects for the patients with epilepsy, especially DRE. Herein we review the recent evidence supporting the role of inflammation in the development and perpetuation of seizures, and also discuss the recent achievements in modulation of inflammation and immunotherapy applied to the treatment of epilepsy. Apart from medical therapy, we also discuss the influences of surgery, ketogenic diet, and electroconvulsive therapy on immunity and inflammation in DRE patients. Taken together, a promising perspective is suggested for future immunomodulatory therapies in the treatment of patients with DRE.
Immunity; Inflammation; Drug-Resistant Epilepsy; Auto-antibodies; Cytokines.
The neurological movement disorder dystonia is an umbrella term for a heterogeneous group of related conditions where at least 20 monogenic forms have been identified. Despite the substantial advances resulting from the identification of these loci, the function of many DYT gene products remains unclear. Comparative genomics using simple animal models to examine the evolutionarily conserved functional relationships with monogenic dystonias represents a rapid route toward a comprehensive understanding of these movement disorders. Current studies using the invertebrate animal models Caenorhabditis elegans and Drosophila melanogaster are uncovering cellular functions and mechanisms associated with mutant forms of the well-conserved gene products corresponding to DYT1, DYT5a, DYT5b, and DYT12 dystonias. Here we review recent findings from the invertebrate literature pertaining to molecular mechanisms of these gene products, torsinA, GTP cyclohydrolase I, tyrosine hydroxylase, and the alpha subunit of Na+/K ATPase, respectively. In each study, the application of powerful genetic tools developed over decades of intensive work with both of these invertebrate systems has led to mechanistic insights into these human disorders. These models are particularly amenable to large-scale genetic screens for modifiers or additional alleles, which are bolstering our understanding of the molecular functions associated with these gene products. Moreover, the use of invertebrate models for the evaluation of DYT genetic loci and their genetic interaction networks has predictive value and can provide a path forward for therapeutic intervention.
Drosophila; C. elegans; torsinA; GTP-cyclohydrolase 1; Na+/K+ ATPase a3 subunit.
Focal dystonias are dystonias that affect one part of the body, and are sometimes task-specific. Brain imaging and transcranial magnetic stimulation techniques have been valuable in defining the pathophysiology of dystonias in general, and are particularly amenable to studying focal dystonias. Over the past few years, several common themes have emerged in the imaging literature, and this review summarizes these findings and suggests some ways in which these distinct themes might all point to one common systems-level mechanism for dystonia. These themes include (1) the role of premotor regions in focal dystonia, (2) the role of the sensory system and sensorimotor integration in focal dystonia, (3) the role of decreased inhibition/increased excitation in focal dystonia, and (4) the role of brain imaging in evaluating and guiding treatment of focal dystonias. The data across these themes, together with the features of dystonia itself, are consistent with a hypothesis that all dystonias reflect excessive output of postural control/stabilization systems in the brain, and that the mechanisms for dystonia reflect amplification of an existing functional system, rather than recruitment of the wrong motor programs. Imaging is currently being used to test treatment effectiveness, and to visually guide treatment of dystonia, such as placement of deep brain stimulation electrodes. In the future, it is hoped that imaging may be used to individualize treatments across behavioral, pharmacologic, and surgical domains, thus optimizing both the speed and effectiveness of treatment for any given individual with focal dystonia.
Dystonia; fMRI; DTI; PET; TMS; MEG; posture; basal ganglia; premotor; cerebellum; botulinum toxin; DBS.
The majority of studies investigating the molecular pathogenesis and cell biology underlying dystonia have been performed in individuals with primary dystonia. This includes monogenic forms such as DYT1and DYT6 dystonia, and primary focal dystonia which is likely to be multifactorial in origin. In recent years there has been renewed interest in non-primary forms of dystonia including the dystonia-plus syndromes and heredodegenerative disorders. These are caused by a variety of genetic mutations and their study has contributed to our understanding of the neuronal dysfunction that leads to dystonia These findings have reinforced themes identified from study of primary dystonia including abnormal dopaminergic signalling, cellular trafficking and mitochondrial function. In this review we highlight recent advances in the understanding of the dystonia-plus syndromes and heredodegenerative dystonias.
Dystonia- plus syndrome; Secondary dystonia; Molecular pathogenesis; Neurodegeneration; Mitochondria.
Musicians’ dystonia is a task-specific and painless loss of motor control in a previously well-executed task. It is increasingly recognized in the medical and musical community. Recent advances in neuroimaging, transcranial magnetic stimulation and novel techniques in electroencephalography have shed light on its underlying pathophysiology. To date, a deranged cortical plasticity leading to abnormal sensorimotor integration, combined with reduced inhibition across several levels of the motor pathway are likely mechanisms.This paper reviews the various phenomenology of musician’s dystonia across keyboard, string, brass, flute and drum players. Treatment is often challenging. Medical therapies like botulinum toxin injection and rehabilitation method with sensorimotor training offer symptomatic relief and return to baseline performance to some musicians.
Botulinum toxin; cortical plasticity; dystonia; musician; rehabilitation; trihexyphenidyl.
A strong association between dystonia and tremor has been known for more than a century. Two forms of tremor in dystonia are currently recognized: 1) dystonic tremor, which is tremor produced by dystonic muscle contraction and 2) tremor associated with dystonia, which is tremor in a body part that is not dystonic, but there is dystonia elsewhere. Both forms of tremor in dystonia frequently resemble essential tremor or another pure tremor syndrome (e.g., isolated head and voice tremors and task-specific writing tremor), and relationships among these tremor disorders have long been debated. Misdiagnosis is common because mild dystonia is frequently overlooked in patients with tremor. It is now clear that essential tremor is a syndrome, not a specific disease, and the use of essential tremor as a specific clinical diagnosis is arguably an impediment to elucidating this and other pure tremor syndromes and their relationship to dystonia. A new classification, primary tremor, is proposed and would be used for any disorder in which tremor is the sole or principal abnormality with no identifiable etiology other than possible genetic inheritance. This classification scheme would facilitate tremor research by moving the focus from the narrow question “Is it essential tremor?” to a broader consideration of what genetic and environmental factors cause primary tremor disorders, and how do they relate to dystonia and other neurological disorders.
Dystonia; essential tremor; tremor.
The focal dystonia benign essential blepharospasm (BEB) affects as many as 40,000 individuals in the United States. This dystonia is characterized by trigeminal hyperexcitability, photophobia, and most disabling of the symptoms, involuntary spasms of lid closure that can produce functional blindness. Like many focal dystonias, BEB appears to develop from the interaction between a predisposing condition and an environmental trigger. The primary treatment for blepharospasm is to weaken the eyelid-closing orbicularis oculi muscle to reduce lid spasms. There are several animal models of blepharospasm that recreate the spasms of lid closure in order to investigate pharmacological treatments to prevent spasms of lid closure. One animal model attempts to mimic the predisposing condition and environmental trigger that give rise to BEB. This model indicates that abnormal interactions among trigeminal blink circuits, basal ganglia, and the cerebellum are the neural basis for BEB.
Basal ganglia; blepharospasm; blink; cerebellum; motor adaptation; trigeminal.
Our understanding of the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) continues to grow considerably. In addition to the core syndromes of pantothenate kinase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2), several other genetic causes have been identified (including FA2H, C19orf12, ATP13A2, CP and FTL). In parallel, the clinical and pathological spectrum has broadened and new age-dependent presentations are being described. There is also growing recognition of overlap between the different NBIA disorders and other diseases including spastic paraplegias, leukodystrophies and neuronal ceroid lipofuscinosis which makes a diagnosis solely based on clinical findings challenging. Autopsy examination of genetically-confirmed cases demonstrates Lewy bodies, neurofibrillary tangles, and other hallmarks of apparently distinct neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease. Until we disentangle the various NBIA genes and their related pathways and move towards pathogenesis-targeted therapies, the treatment remains symptomatic.
Our aim here is to provide an overview of historical developments of research into iron metabolism and its relevance in neurodegenerative disorders. We then focus on clinical features and investigational findings in NBIA and summarize therapeutic results reviewing reports of iron chelation therapy and deep brain stimulation. We also discuss genetic and molecular underpinnings of the NBIA syndromes.
Ceramide; dystonia; iron; NBIA; parkinsonism; MPAN; PKAN; PLA2G6.
The activity of locus coeruleus (LC) neurons has been extensively investigated in a variety of behavioural states. In fact this norepinephrine (NE)-containing nucleus modulates many physiological and pathological conditions including the sleep-waking cycle, movement disorders, mood alterations, convulsive seizures, and the effects of drugs such as psychostimulants and opioids. This review focuses on the modulation exerted by central NE pathways on the behavioural and neurotoxic effects produced by the psychostimulant methamphetamine, essentially the modulation of the activity of mesencephalic dopamine (DA) neurons. In fact, although NE in itself mediates some behavioural effects induced by methamphetamine, NE modulation of DA release is pivotal for methamphetamine-induced behavioural states and neurotoxicity. These interactions are discussed on the basis of the state of the art of the functional neuroanatomy of central NE- and DA systems. Emphasis is given to those brain sites possessing a remarkable overlapping of both neurotransmitters.
Behaviour; Dopamine; Locus Coeruleus; Methamphetamine; Neurochemistry; Norepinephrine; Substantia Nigra; Drugs of Abuse.
The multiplicity of peptidergic receptors and of the transduction pathways they activate offers the possibility of important advances in the development of specific drugs for clinical treatment of central nervous system disorders. Among them, retinal ischemia is a common clinical entity and, due to relatively ineffective treatment, remains a common cause of visual impairment and blindness. Ischemia is a primary cause of neuronal death, and it can be considered as a sort of final common pathway in retinal diseases leading to irreversible morphological damage and vision loss. Neuropeptides and their receptors are widely expressed in mammalian retinas, where they exert multifaceted functions both during development and in the mature animal. In particular, in recent years somatostatin and pituitary adenylate cyclase activating peptide have been reported to be highly protective against retinal cell death caused by ischemia, while data on opioid peptides, angiotensin II, and other peptides have also been published. This review provides a rationale for harnessing the peptidergic receptors as a potential target against retinal neuronal damages which occur during ischemic retinopathies.
Angiotensin; glutamate release; neuronal death; PACAP; peptide receptors; opioid peptides; somatostatin.
A considerable amount of evidence shows that reactive oxygen species (ROS) in the mammalian brain are directly responsible for cell and tissue function and dysfunction. Excessive reactive oxygen species contribute to various conditions including inflammation, diabetes mellitus, neurodegenerative diseases, tumor formation, and mental disorders such as depression. Increased intracellular calcium levels have toxic roles leading to cell death. However, the exact connection between reactive oxygen production and high calcium stress is not yet fully understood. In this review, we focus on the role of reactive oxygen species and calcium stress in hypothalamic arcuate neurons controlling feeding. We revisit the role of NPY and POMC neurons in the regulation of appetite and energy homeostasis, and consider how ROS and intracellular calcium levels affect these neurons. These novel insights give a new direction to research on hypothalamic mechanisms regulating energy homeostasis and may offer novel treatment strategies for obesity and type-2 diabetes.
Oxidative stress; Reactive oxygen species; NPY; AgRP; POMC; Ghrelin; Leptin; Mitochondrial respiration; Hypothalamic appetite control.
Much attention has been devoted to neurodegenerative diseases involving redox processes. This review comprises an update involving redox processes reported in the considerable literature in recent years. The mechanism involves reactive oxygen species and oxidative stress, usually in the brain. There are many examples including Parkinson’s, Huntington’s, Alzheimer’s, prions, Down’s syndrome, ataxia, multiple sclerosis, Creutzfeldt-Jacob disease, amyotrophic lateral sclerosis, schizophrenia, and Tardive Dyskinesia. Evidence indicates a protective role for antioxidants, which may have clinical implications. A multifaceted approach to mode of action appears reasonable.
Redox; neurodegenerative diseases; reactive oxygen species; oxidative stress.