CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 10, Issue 1, 2011

Parkinson's Disease: Kinase Busters to the Rescue? Parkinson's disease (PD) was first described in the essay entitled “An Essay of the Shaking Palsy” by James Parkinson in 1817. PD is the most common neurodegenerative movement disorder, whose neuropathological hallmarks are characterized by progressive and profound loss of neuromelanin-containing dopaminergic neurons in the substantia nigra pars compacta with the presence of eosinophilic intracytoplasmic, proteinaceous inclusions termed Lewy bodies and dystrophic Lewy neurites in surviving neurons. Although neuronal cell loss in the substantia nigra pars compacta is pronounced, there is widespread neurodegeneration in the CNS with the pars compacta being involved in midstages of the disease. Clinical manifestations of this complex disease include motor impairments involving resting tremor, bradykinesia, postural instability, gait difficulty and rigidity, along with non-motoric symptoms like autonomic, cognitive, and psychiatric problems. While the majority of PD cases are sporadic, ∼10% have been linked to mutations in specific genes, particularly the gene encoding leucine-rich repeat kinase 2 (LRRK2) in which the enzyme's activity is increased. In vitro studies have also suggested a role for mutant forms of LRRK2 in neurotoxicity. In a new study reported in Nature Medicine, Lee and colleagues have investigated the importance of these findings in vivo and identified LRRK2 kinase inhibitors that reduce neurotoxicity in mice. The authors first screened 84 commercially available kinase and phosphatase inhibitors for in vitro activity against LRRK2. Of these, eight compounds were found to decrease LRRK2 autophosphorylation. Their potency was similar against the wild-type enzyme and a mutated version (G2019S) that is a common cause of familial and sporadic PD. The compounds included an inhibitor of RAF1 (a kinase closely related to LRRK2) and indirubin-3'-monooxime, an inhibitor of glycogen synthase kinase 3β. In cultured primary cortical neurons, over-expression of the G2019S mutant led to cell death. This effect was limited by the study compounds, but not by kinase inhibitors that do not block LRRK2 activity. Finally, the group devised a mouse model of LRRK2 toxicity in which the PD-linked mutant version of the protein was introduced via viral vector into the substantia nigra, the brain region most affected by PD. Peripheral injection of the test drugs decreased dopaminergic neuron loss caused by the transgene compared to injection of vehicle. Over-expression of wild-type LRRK2 or a kinase-dead form of the mutant enzyme did not have adverse effects. Several of the molecules used by the Johns Hopkins team, including the indolinone GW5074 and indirubin-3'-monooxime may be good starting points for drug development, given their high affinity for LRRK2. Whether or not the neuroprotective action of these compounds stems from the originally intended targets of many of the molecules, such as RAF1 and glycogen synthase kinase 3β, rather or in addition to LRRK2 inhibition, remains to be established. In addition, the in vivo model used in Lee et al. is based on over-expression of mutant LRRK2, which may create a bias toward showing a therapeutic effect for kinase inhibitors. Although this may not capture what goes on in PD patients, the model does feature degeneration of dopaminergic neurons. As with CNS drugs in general, selectivity, tolerability, and blood-brain barrier penetration present obstacles. These caveats notwithstanding, the findings highlight a therapeutic potential for targeting aberrant LRRK2 kinase activity in PD, and could provide model to approach other genetic mutations that have been associated with this disorder.

Inflammatory processes in the central nervous system (CNS) are of acute relevance to the pathogenesis and progression of several important neurological disorders. While multiple sclerosis (MS) is often quoted as one of the most striking examples of an inflammatory neurodegenerative condition, it is now widely recognized that inflammatory processes, particularly the innate immune responses, play a crucial role also in the pathogenesis of several other neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). In addition, the clinical outcome of cerebrovascular disorders including stroke, and of acute brain and spinal cord injury is determined to a large extent by inflammatory processes which control resolution of damage, and subsequent repair. Thus, understanding inflammation and particularly the first steps in the process i.e. the innate inflammatory response in the CNS, is of central importance to understanding the nature of major neurological problems, and thus to effectively design ways to control them and treat disease. The neurodegenerative disorders mentioned above in which innate inflammation plays a crucial role represent the majority of chronic neurodegenerative disorders. When examined for their impact on disability-adjusted life years, a measure used by the World Health Organization [1] to assess the impact of various diseases, cerebrovascular disorders including stroke account for more than half the disease burden, while neurodegenerative conditions including AD, PD, and MS make up for another 15%. The contribution especially by various dementias to the global disease burden is expected to sharply rise over the next decades, due to, for example, the ageing of the population. Different from stroke or traumatic brain injury, the neurodegenerative conditions such as AD, PD and MS are not immediate killers, but rather these disorders reduce the quality of life over a much longer period of time. The worldwide prevalence of MS for example is estimated at around 0.01%, but its worldwide impact on disability-adjusted life years is ten times higher. Also since several neurological disorders are particularly prevalent in the more affluent regions of the world, with ageing populations, they represent targets of strong interest to the pharmaceutical industry. While neurological diseases account for about 6% of the global disease burden, the CNS drug market represents about twice this percentage of the global pharmaceutical market. The global market of MS drugs rapidly approaches 10 billion US dollars, which is around 1% of the total worldwide sales of pharmaceutics, ten times over what would be expected based on mere disease burden. Neurological diseases are clearly very attractive targets for drug development. This special issue in CNS & Neurological Disorders - Drug Targets, aims to reflect our growing understanding of innate immune processes in the brain and spinal cord. These processes are vital to maintain homeostasis in the CNS, to control infections and tumours that may emerge, and to initiate repair processes and regeneration after trauma. The inflammatory processes that will be discussed are pivotal to a number of neurological and neurodegenerative disorders. When considering innate immune responses in the CNS, one particular cell type attracts immediate attention. It is the brain macrophage, known as microglia. This relatively small cell that populates the entire CNS is a true sentinel. Microglia spend their life exploring their individual territories in the tissue. Like the brain they protect, it is used to an 8-hour working day, which is the time it takes for a single microglia to fully scan its environment. Microglia possess an impressive array of receptors to sense environmental signals, and they rapidly respond when they encounter anything out of the ordinary within their territory, be it the presence of danger or a stranger. Apart from the obvious role of microglia, however, essentially all cell types in the CNS are involved in controlling inflammatory processes. Astrocytes, oligodendrocytes, and also neurons themselves are all actively engaged in continuous surveillance and communication. A bewildering collection of receptors and ligands are expressed by all these cells, and are used to initiate, regulate, and inhibit inflammatory processes. In the first chapter of this issue, Jeffrey Bajramovic sheds light on the nature of cellular receptors involved in controlling inflammatory responses in the CNS, and the ligands that exist for these receptors. The well-known Toll-like receptors are among them, but there are many more receptors involved. Special attention is drawn to adenosine receptors, which have only recently been recognized for their pivotal contribution to inflammatory processes in the CNS. In addition, this first contribution emphasizes that many of the receptors involved in inflammatory pathways do not merely stimulate inflammatory responses by microglia, but are essential to the functions of other neural cells as well, and quite often crucial in inhibiting inflammation rather than stimulating it. This particular point is taken further in the second chapter, in which Philippe Gasque and colleagues introduce neuroimmune regulatory proteins. This group of surface-expressed proteins can be found on many different types of cells, and perform an array of intriguing functions. They regulate phagocytic activity by microglia, sequester and neutralize pro-inflammatory factors, and instigate recruitment of stem cells. Like several of the receptors described in the first chapter, neuroimmune regulatory proteins offer novel options as therapeutic targets. In chapter 3, ion channels are highlighted as another group of possible therapeutic targets. Stephen Skaper scrutinizes the role of microglial ion channels in different neuroinflammatory conditions. Evidence is presented for a close involvement of these ion channels in processes leading to neurodegeneration, including the processes culminating in AD or MS. This chapter supports the idea that blocking ion channels may help to inhibit exaggerated or chronic inflammation in the CNS, thus proving clearly defined targets for anti-inflammatory intervention. In the case of AD, both epidemiological and genetic evidence point to a contribution of inflammation to the disease process. Yet, antiinflammatory intervention in established disease has not yet produced the effects hoped for. In chapter 4, Jeroen Hoozemans and colleagues examine the role of inflammation in AD. Among the first to recognize the inflammatory component in the pathogenesis of AD, they examine current strategies to apply anti-inflammatory drugs to AD. This chapter makes the point that some of the key inflammatory events in AD actually precede clinical manifestation. It is therefore suggested that anti-inflammatory intervention may be more successful when applied as an early, preventive strategy. That anti-inflammatory strategies, i.e. simply blocking the activity of for example microglia, may not always be the best option, is further illustrated in chapter 5, which focuses on MS. In this chapter, Sandra Amor and Hans van Noort and colleagues explain how the destructive inflammatory process that causes MS is actually preceded by an initial stage of local mild inflammation in brain tissue which appears to be aimed at repair. Likely triggered by oligodendrocyte stress, microglia under these conditions do become activated, but not in a traditional destructive way. Instead, local signals, notably including small heat shock proteins, stimulate microglia to produce anti-inflammatory and reparative mediators, and almost all of these events of microglial activation appear to resolve spontaneously. Clearly, blocking microglial function at this stage would likely cause more harm than good....

Innate immune responses in the central nervous system must be tightly regulated as unrestrained activation generates a chronic inflammatory environment that can contribute to neurodegeneration and autoimmunity. Microglia express a wide variety of receptors of the innate immune system and are competent responders to danger. Toll-like receptor-, NOD-like receptor- and RIG1-like receptor mediated activation of microglia leads to the production of pro-inflammatory cytokines and to the upregulation of molecules implicated in activation of the adaptive immune system. Activated microglia are a characteristic feature of many neuroinflammatory disorders and they represent an attractive therapeutic target. This review describes the mechanisms that are at play to restrain microglia activation under homeostatic conditions, such as CD172a, CD200R, SIGIRR and TREM2-mediated signaling, as well as dynamic inhibitory mechanisms that are at play during inflammatory conditions, such as adenosine receptor-mediated signaling. In addition, intracellular activating and inhibitory signaling cascades are summarized in detail and their therapeutic potential is analyzed.

Innate immunity is an arsenal of molecules and receptors expressed by professional phagocytes, glial cells and neurons and involved in host defence and clearance of toxic and dangerous cell debris. However, any uncontrolled innate immune responses within the central nervous system (CNS) are widely recognized as playing a major role in the development of autoimmune disorders and neurodegeneration, with multiple sclerosis (MS) and Alzheimer's diseases (AD) being primary examples. Critically, neuroimmune regulatory proteins (NIReg) may control the adverse immune responses in health and diseases. NIRegs are found mainly on neurons, glia, endothelia and ependymal cells and include GPI-anchored molecules (CD24, CD90, complement regulators CD55 and CD59), molecules of the immunoglobulin superfamily (siglec CD22, Siglec 10, CD200, ICAM-5) and others (CD47, fractalkine, TAM receptor tyrosine kinase and complement C3a and factor H). These regulators modulate the innate immune response in the CNS and for instance critically control the level of phagocytosis and inflammation engaged by resident microglia and infiltrating immune cells. Others will sequester and neutralize proinflammatory molecules such as HMGB1 and DNA. Moreover, some NIRegs can instigate the recruitment of stem cells to mediate tissue repair. In the absence of these regulators, when neurons die by apoptosis, become infected or damaged, microglia and infiltrating immune cells are free to cause injury and an adverse inflammatory response in acute and chronic settings. The therapeutic applications of NIRegs should be exploited given their natural and selective healing properties.

Under pathological conditions microglia (resident CNS immune cells) become activated, and produce reactive oxygen and nitrogen species and pro-inflammatory cytokines: molecules that can contribute to axon demyelination and neuron death. Because some microglia functions can exacerbate CNS disorders, including stroke, traumatic brain injury, progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, and several retinal diseases, controlling their activation might ameliorate immune-mediated CNS disorders. A growing body of evidence now points to ion channels on microglia as contributing to the above neuropathologies. For example, the ATP-gated P2X7 purinergic receptor cation channel is up-regulated around amyloid β-peptide plaques in transgenic mouse models of Alzheimer's disease and co-localizes to microglia and astrocytes. Upregulation of the P2X7 receptor subtype on microglia occurs also following spinal cord injury and after ischemia in the cerebral cortex of rats, while P2X7 receptor-like immunoreactivity is increased in activated microglial cells of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. Utilizing neuron/microglia co-cultures as an in vitro model for neuroinflammation, P2X7 receptor activation on microglia appears necessary for microglial cell-mediated injury of neurons. A second example can be found in the chloride intracellular channel 1 (CLIC1), whose expression is related to macrophage activation, undergoes translocation from the cytosol to the plasma membrane (activation) of microglia exposed to amyloid β-peptide, and participates in amyloid β-peptide-induced neurotoxicity through the generation of reactive oxygen species. A final example is the small-conductance Ca2+/calmodulin-activated K+ channel KCNN4/KCa3.1/SK4/IK1, which is highly expressed in rat microglia. Lipopolysaccharide-activated microglia are capable of killing adjacent neurons in co-culture, and show markedly reduced toxicity when treated with an inhibitor of KCa3.1 channels. Moreover, blocking KCa3.1 channels mitigated the neurotoxicity of amyloid β-peptide-stimulated microglia. Excessive microglial cell activation and production of potentially neurotoxic molecules, mediated by ion channels, may thus constitute viable targets for the discovery and development of neurodegenerative disease therapeutics. This chapter will review recent data that reflect the prevailing approaches targeting neuroinflammation as a pathophysiological process contributing to the onset or progression of neurodegenerative diseases, with a focus on microglial ion channels and their neuroprotective potential.

Epidemiological studies suggest that systemic use of non-steroidal anti-inflammatory drugs (NSAIDs) can prevent or retard the development of Alzheimer's disease (AD). However, clinical trials investigating the effects of NSAIDs on AD progression have yielded mixed or inconclusive results. The aim of this review is to distinguish the role of inflammation and the molecular targets of NSAIDs in the different stages of AD pathology. AD brains are characterized by extracellular deposits of β-amyloid protein and intraneuronal accumulation of hyperphosphorylated tau protein. Already in the early stages of AD pathology β-amyloid protein deposits are associated with inflammatory proteins and microglia, the brain resident macrophages. Recently, two genome-wide association studies identified new genes that are associated with an increased risk of developing AD. These genes include CLU and CR1 which encode for clusterin and complement receptor 1 respectively. Both genes are involved in the regulation of inflammation. This strongly indicates that inflammation plays a central role in the aetiology of AD. In this review we will show that the primary targets of NSAIDs are involved in a pathological stage that precedes the clinical appearance of AD. The early, preclinical involvement of inflammation in AD explains why patients with clinical signs of AD do not benefit from anti-inflammatory treatment and suggests that NSAIDs, rather than having a direct therapeutic effect, may have preventive effects.

For the development of novel central nervous system (CNS) drugs to promote neuroprotection, it is helpful to gain a better understanding of natural neuroprotective phenomena. Microglia play key roles in endogenous neuroprotective pathways and their activation is a common theme in several neurodegenerative disorders. Yet, while it is widely appreciated that activated microglia can have neuroprotective qualities, their contribution to tissue destruction and neurodegeneration within the CNS is equally obvious. This apparent duality in microglial functions renders it difficult to determine whether microglial activation under certain conditions is something to counteract, or to support. Also, it is far from clear which microglial functions support neuroprotection, and which support destruction. Here, we review evidence that a special phenomenon in multiple sclerosis (MS) patients offers a unique possibility to study polarized protective functions of microglia. During MS, small clusters of activated microglia frequently emerge throughout normal appearing white matter. Several lines of evidence suggest that these clusters, which are referred to as preactive MS lesions, represent a reversible first stage in the development of inflammatory, demyelinating MS lesions. Progression onto this final destructive stage may occur but, importantly, does not seem to be inevitable. Instead, resolution of preactive lesions is probably the rule rather than the exception. For as long as preactive lesions remain non-infiltrated by peripheral lymphocytes, they reflect a local neuroprotective and reparative response. A critical factor in the emergence of preactive lesions is oligodendrocyte stress, which leads to accumulation of factors such as small heat shock proteins. At least some of these can induce an immune-regulatory response in neighboring microglia. A closer understanding of the molecular make-up of preactive MS lesions, of the signals which cause microglial activation, and of the protective mediators produced by microglia in this context, will help uncover novel clues for neuroprotective therapeutic strategies with relevance for clinical applications well beyond the field of MS alone.

The nervous system is a unique network of different cell types and comprises a variety of proteins, lipids, and carbohydrates that have an important interplay with all major organs in the body. Homeostatic regulation of nervous tissue turnover must be carefully controlled, taking into account interactions of the nervous, endocrine, and immune systems. Clinical conditions affecting the nervous system range from mild cognitive perturbations such as headache, to life-threatening acute courses such as meningitis and glioblastoma, and to chronic neurodegenerative diseases such as multiple sclerosis. One unifying feature in normal developmental or homeostatic functions and clinical dysfunctions within the nervous system is redox regulation, with an imbalance in oxidative/carbonyl stress versus antioxidants being characteristic of pathological conditions. In this review we consider the state of current knowledge regarding structural, genetic, proteomic, histopathological, clinical, and therapeutic perspectives of oxidative and carbonyl stress within the nervous system.

Microglia, the tissue macrophages of the brain, have under healthy conditions a resting phenotype that is characterized by a ramified morphology. With their fine processes microglia are continuously scanning their environment. Upon any homeostatic disturbance microglia rapidly change their phenotype and contribute to processes including inflammation, tissue remodeling, and neurogenesis. In this review, we will address functional phenotypes of microglia in diverse brain regions and phenotypes associated with neuroinflammation, neurogenesis, brain tumor homeostasis, and aging.

Major Depressive Disorder (MDD) is an extremely disabling, chronic and recurrent disease. Moreover, subthreshold depressive symptoms often persist during periods of apparent remission. Such symptoms include sleep disturbances, sexual dysfunction, weight gain, fatigue, disinterest, anxiety, and/or emotional blunting, which do not often respond to available antidepressant treatments. Agomelatine is a melatonergic agonist (at both MT1 and MT2 receptors) and serotonin 2C (5-HT2C) receptor antagonist. Agomelatine should be particularly useful in the treatment of MDD because of its unique pharmacological profile, accounting for its effective antidepressant action with a relative lack of serious adverse effects. Several clinical trials confirmed the antidepressant efficacy of agomelatine in patients with MDD, with significant efficacy even in severe manifestations of disease and on residual subtreshold symptoms. This compound showed a relative early onset of action as well as an excellent safety and tolerability profile linked to a low discontinuation rate in MDD patients. Moreover, some data suggest that agomelatine has not only antidepressant effects but also anxiolytic effects, with a potential benefit both on anxiety symptoms associated with MDD and in the treatment of generalised anxiety disorder. This review will summarise the role of the melatonergic system in MDD and will describe the characteristics of agomelatine, focusing on its efficacy and safety in the treatment of MDD.

The treatment of Alzheimer's disease is undoubtedly one of the greatest challenges of modern medicine and pharmacology. Affecting millions of people, Alzheimer's disease has become a major social problem. Several theories have been proposed to account for its pathogenesis. Possibly, the “amyloid cascade hypothesis” is the dominant one. However, the “inflammation hypothesis” also contributes to the pathogenesis of the disease. Thus, this study intends to describe the role of neuroinflammation in Alzheimer's disease, regarding its cellular and molecular components, and to examine if the use of non-steroidal anti-inflammatory drugs could be an effective “weapon” in the battle against it.

Neisseria meningitidis (N. meningitidis) causes sepsis, epidemic meningitis, and sometimes also meningoencephalitis. Despite early antibiotic treatment, mortality and morbidity remain significant. We present recent studies on meningococcal disease with focus on the pathophysiology caused by bacterial virulence factors and the host immune responses. The bacterial outer membrane lipopolysaccharide and non-lipopolysaccharide components are related to meningococcal adhesion and invasion, while the host immune reactions propagate inflammation and neurodegeneration. Hence, bacterium-host interactions are key determinants of the clinical course and risk of fatal outcome. Accordingly, successful treatment of severe meningococcal disease requires not only antibiotics but also adjuvants targeting the released endotoxins and the host immune/inflammatory responses. This review highlights the most recent data and current knowledge on molecular mechanisms of meningococcal disease and explains how host immune responses ultimately may aggravate neuropathology and the clinical prognosis. Within this context, particular importance is paid to the endotoxic components that provide potential drug targets for novel neuroprotective adjuvants, which are needed in order to improve the clinical management of meningoencephalitis and patient prognosis.