CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 9, Issue 2, 2010

Depression is one of the common prevalent forms of neuropsychiatric disorder and a leading cause for morbidity and mortality in the world. According to the World Health Organization, major depression is projected to become an important contributor to global public health problems by 2020. Despite the significant progress achieved in the pharmacotherapy of depression in recent years, limitations with current treatments still exist in terms of clinical efficacy, delayed onset of action, and associated side effects. In addition, patients with co-morbid depression and anxiety are not effectively treated with available antidepressants. One solution could be to target additional brain receptors and associated neuronal mechanisms in preclinical models for better understanding of the specific aspects of this unique type of depression. Consequently, the novel treatments could be used against co-morbid depression. Emerging evidence suggests that the Wistar Kyoto (WKY) rat strain is a unique preclinical model for neuropsychiatric dysfunction. Thus, the neurobiology of its phenotype could provide critical understanding of major depression and anxiety that leads to new therapeutics. Previous research indicates that the k-opioid receptor (KOR) system has been implicated in depression, and KOR antagonists have been investigated as potential antidepressants. In the present study, Carr and colleagues have proposed the WKY rat strain as a putative genetic model of co-morbid depression and anxiety. Using preclinical testing methods, the authors clearly demonstrated selective antidepressant efficacy of KOR antagonists (nor-binaltorphimine and DIPPA) in WKY rats compared to other rat strains. Furthermore, brain regions such as nucleus accumbens and piriform cortex as sites of action for KOR antagonists for antidepressant efficacy have been identified using c-fos expression, a marker for neuronal activation. Additionally, application of nor-binaltorphimine into the piriform cortex produced antidepressant-like effects in WKY rats, highlighting this brain region in the antidepressant-like effects to KOR antagonists. Overall, these observations convincingly support the use of WKY rat as a model of mood disorders involving KOR hyperactivity, and provide behavioral and biochemical evidence that KOR antagonists could be developed as novel antidepressants. Nevertheless, additional studies should add more information to address whether the KOR system is involved in the anxiogenic component of the WKY phenotype. Thus, genetic animal models and associated brain targets that display a unique neurobiological profile can be investigated to advance the development of effective treatments for co-morbid depression and anxiety in upcoming years.

Few topics in the field of Alzheimer's disease (AD) research have brought about the level of excitement and interest as the role of inflammation and immunity in the pathobiology and treatment of the disease. In this special issue of the journal, experts in the field give their views on how inflammatory processes and the immune system intersect- at both the etiological and treatment levels- with disease biology. Collectively, nearly three decades of work are covered in this special issue, beginning with the first epidemiologic studies that showed an inverse risk relationship between AD and use of non-steroidal anti-inflammatory drugs, and ending with “immunotherapy” approaches and recent studies examining the roles of innate immune cells, including microglia and peripheral mononuclear phagocytes in AD. Despite considerable work in this area, many important questions remain concerning the nature and timing of immune/inflammatory responses in the context of AD, and at what point and how to therapeutically intervene.

Alzheimer's disease imposes a significant public health burden that will only worsen as the population ages. Thus, there is considerable motivation to develop effective strategies to treat, or more ideally, prevent the disease. Epidemiologic evidence has suggested that non-steroidal anti-inflammatory drugs (or NSAIDs) may be neuro-protective. However, this evidence is controversial. Observational studies in humans have found that the use of NSAIDs is associated with a lower risk of developing Alzheimer's disease. By contrast, randomized trials have reported that NSAIDs are not effective in treating patients with clinically established disease nor in preventing the onset of dementia among those who are cognitively normal or have mild cognitive impairment. In this article, we review the existing epidemiologic evidence on the relationship between NSAIDs and Alzheimer's disease and discuss several hypotheses to explain the divergent findings.

Alzheimer's disease (AD) is accompanied by an activation of the innate immune system, and many epidemiological studies have shown reduced risk for dementia or AD associated with chronic consumption of non-steroidal anti-inflammatory drugs (NSAIDS). These observations led to animal model studies to test the hypothesis that NSAIDs can be disease-modifying for some aspects of AD pathogenesis. NSAIDS cannot only suppress inflammatory targets, which could contribute to neuroprotection, they also slow amyloid deposition by mechanisms that remain unclear. Several large clinical trials with NSAID therapies with AD subjects have failed, and cyclooxygenase-2 does not appear to be a useful target for disease modifying therapy. However, there may be apolipoprotein E E4 pharmacogenomic effects and a real but delayed positive signal in a large primary prevention trial with naproxen. This encourages researchers to re-address possible mechanisms for a stage-dependent NSAID efficacy, the subject of this review.

As the number of elderly individuals rises, Alzheimer's disease (AD), marked by amyloid-β deposition, neurofibrillary tangle formation, and low-level neuroinflammation, is expected to lead to an ever-worsening socioeconomic burden. AD pathoetiologic mechanisms are believed to involve chronic microglial activation. This phenomenon is associated with increased expression of membrane-bound CD40 with its cognate ligand, CD40 ligand (CD40L), as well as increased circulating levels of soluble forms of CD40 (sCD40) and CD40L (sCD40L). Here, we review the role of this inflammatory dyad in the pathogenesis of AD. In addition, we examine potential therapeutic strategies such as statins, flavonoids, and human umbilical cord blood transplantation, all of which have been shown to modulate CD40-CD40L interaction in mouse models of AD. Importantly, therapeutic approaches focusing on CD40-CD40L dyad regulation, either alone or in combination with amyloid-β immunotherapy, may provide for a safe and effective AD prophylaxis or treatment in the near future.

One hundred and fifty years have elapsed since the original discovery of the microglial cell by Virchow. While this cell type has been well studied, the role of microglia in the pathology of many central nervous system diseases still remains enigmatic. It is widely accepted that microglial-mediated inflammation contributes to the progression of Alzheimer's disease (AD); however, the precise mechanisms through which these cells contribute to AD-related inflammation remains to be elucidated. In the AD brain, microglial cells are found in close association with amyloid β (Aβ) deposits. Histological examination of AD brains as well as cell culture studies have shown that the interaction of microglia with fibrillar Aβ leads to their phenotypic activation. The conversion of these cells into a classically ‘activated’ phenotype results in production of chemokines, neurotoxic cytokines and reactive oxygen and nitrogen species that are deleterious to the CNS. However, microglia also exert a neuroprotective role through their ability to phagocytose Aβ particles and clear soluble forms of Aβ. These cells have been documented to play integral roles in tissue repair and inflammation, and in recent years it has been appreciated that this cell type is capable of facilitating a more complex response to pathogens by changing their activation status. A variety of new findings indicate that their role in the central nervous system is far more complex than previously appreciated. In this review we discuss the role of microglia in the normal brain and their phenotypic heterogeneity and how this may play a role in ADrelated pathophysiology. We touch on what is known about their ability to recognize and clear Aβ peptides as well as more controversial topics, including various activation states of microglia and the ability of peripheral macrophages or monocytes to infiltrate the brain.

Alzheimer's disease (AD) is associated with a significant neuroinflammatory component. Mononuclear phagocytes including monocytes and microglia are the principal cells involved, and they accumulate at perivascular sites of β-amyloid (Aβ) deposition and in senile plaques. Recent evidence suggests that mononuclear phagocyte accumulation in the AD brain is dependent on chemokines. CCL2, a major monocyte chemokine, is upregulated in the AD brain. Interaction of CCL2 with its receptor CCR2 regulates mononuclear phagocyte accumulation in a mouse model of AD. CCR2 deficiency leads to lower mononuclear phagocyte accumulation and is associated with higher brain Aβ levels, specifically around blood vessels, suggesting that monocytes accumulate at sites of Aβ deposition in an initial attempt to clear these deposits and stop or delay their neurotoxic effects. Indeed, enhancing mononuclear phagocyte accumulation delays progression of AD. Here we review the mechanisms of mononuclear phagocyte accumulation in AD and discuss the potential roles of additional chemokines and their receptors in this process. We also propose a multi-step model for recruitment of mononuclear phagocytes into the brain. The first step involves egress of monocyte/microglial precursors from the bone marrow into the blood. The second step is crossing the blood-brain barrier to the perivascular areas and into the brain parenchyma. The final step includes movement of monocytes/microglia from areas of the brain that lack any amyloid deposition to senile plaques. Understanding the mechanism of recruitment of mononuclear phagocytes to the AD brain is necessary to further understand the role of these cells in the pathogenesis of AD and to identify any potential therapeutic use of these cells for the treatment of this disease.

Since the original identification of microglia as a principal player in the brain's innate immune response, microglial activation has been widely studied. Recent studies suggest that microglial responses are heterogeneous, requiring a more precise definition of the functional outcomes of their participation in disease. Similarly to other tissue macrophages, microglia respond to inflammatory or injurious stimuli in the CNS in a pre-programmed manner that is designed to both kill and to set the stage for repair and resolution of the disease. In vitro studies on acute immune responses have provided key information on the initiation, signaling pathways and products of activated macrophages. However, in chronic neurodegenerative diseases such as Alzheimer's disease where in vivo analyses are critical to understanding the long-term disease processes, our knowledge of the integrated tissue immune response and the outcome of this immune activity to neurons and other glia over the extended course of disease is more limited. This is due in part to the complexity of microglial activation states and to the location of microglia in a dense neuronal network. Classical activation, alternative activation and acquired deactivation are each found in the brain during chronic neuroinflammatory diseases and may demonstrate regional differences in expression levels. This review will identify “markers” that can be used to explore inflammatory states in the brain and will discuss the likely functional outcomes when these cytoactive factors are expressed. A broad-based functional view is provided that is designed to more fully explore the balance between inflammo-toxic and inflammo-resolution factors that govern chronic disease progression.

Morbidities of aging and Alzheimer's disease (AD) have been related to defective functions of both T cells and macrophages leading to brain amyloidosis and inflammation. In AD patients, “inflammaging” may be associated with an increase of incompetent memory T cells and inflammatory cytokines produced by macrophages, whereas defective clearance of amyloid-β 1-42 (Aβ) may be related to defective transcription of immune genes necessary for Aβ phagocytosis, β-1,4-mannosyl-glycoprotein 4-β-Nacetylglucosaminyltransferase and Toll-like receptors. However, AD shows considerable heterogeneity of disease manifestations and mechanisms. The approaches to re-balancing Aβ immunity and inflammation are being pursued in transgenic animal models and peripheral blood mononuclear cells of patients. The regulatory signaling pathways of microglial phagocytosis and inflammation involving co-receptors and transforming growth factor-β have been considerably clarified in animal studies. Natural immunostimulating therapies using vitamin D3 and curcuminoids have been developed in macrophages of AD patients. AD patients possess two types of macrophages: a majority has “Type I”, which are improved by curcuminoids and vitamin D3; whereas a minority has “Type II” responding positively to vitamin D3 but not to curcuminoids. Other nutritional substances, such as plant polyphenols and omega-3 fatty acids, may inhibit inflammation and stimulate immunity. More invasive immune approaches involve Aβ vaccine and cytokine antagonists. Increased inflammation may represent the “first hit”, and defective transcription of immune genes the “second hit” in the pathogenesis of AD.

Alzheimer's disease (AD) is a progressive, degenerative disorder of the brain and the most common form of dementia among the elderly. As the population grows and lifespan is extended, the number of AD patients will continue to rise. Current clinical therapies for AD provide partial symptomatic benefits for some patients; however, none of them modify disease progression. Amyloid-β (Aβ) peptide, the major component of senile plaques in AD patients, is considered to play a crucial role in the pathogenesis of AD thereby leading to Aβ as a target for treatment. Aβ immunotherapy has been shown to induce a marked reduction in amyloid burden and an improvement in cognitive function in animal models. Although preclinical studies were successful, the initial human clinical trial of an active Aβ vaccine was halted due to the development of meningoencephalitis in ˜ 6% of the vaccinated AD patients. Some encouraging outcomes, including signs of cognitive stabilization and apparent plaque clearance, were obtained in subset of patients who generated antibody titers. These promising preliminary data support further efforts to refine Aβ immunotherapy to produce highly effective and safer active and passive vaccines for AD. Furthermore, some new human clinical trials for both active and passive Aβ immunotherapy are underway. In this review, we will provide an update of Aβ immunotherapy in animal models and in human beings, as well as discuss the possible mechanisms underlying Aβ immunotherapy for AD.

Pre-clinical and clinical data suggest that the development of a safe and effective anti-amyloid-beta (Aβ) immunotherapy for Alzheimer's disease (AD) will require therapeutic levels of anti-Aβ antibodies, while avoiding proinflammatory adjuvants and autoreactive T cells which may increase the incidence of adverse events in the elderly population targeted to receive immunotherapy. The first active immunization clinical trial with AN1792 in AD patients was halted when a subset of patients developed aseptic meningoencephalitis. The first passive immunotherapy trial with bapineuzumab, a humanized monoclonal antibody against the end terminus of Aβ, also encountered some dose-dependent adverse events during the Phase II portion of the study, vasogenic edema in 12 cases, which were significantly over represented in ApoE4 carriers. The proposed remedy is to treat future patients with lower doses, particularly in the ApoE4 carriers. Currently there are at least five ongoing anti-Aβ immunotherapy clinical trials. Three of the clinical trials use humanized monoclonal antibodies, which are expensive and require repeated dosing to maintain therapeutic levels of the antibodies in the patient. However, in the event of an adverse response to the passive therapy antibody delivery can simply be halted, which may provide a resolution to the problem. Because at this point we cannot readily identify individuals in the preclinical or prodromal stages of AD pathogenesis, passive immunotherapy is reserved for those that already have clinical symptoms. Unfortunately those individuals have by that point accumulated substantial neuropathology in affected regions of the brain. Moreover, if Aβ pathology drives tau pathology as reported in several transgenic animal models, and once established if tau pathology can become self propagating, then early intervention with anti-Aβ immunotherapy may be critical for favorable clinical outcomes. On the other hand, active immunization has several significant advantages, including lower cost and the typical immunization protocol should be much less intrusive to the patient relative to passive therapy. However in the advent of Aβ-antibody immune complex-induced adverse events the patients will have to receive immuno-suppressive therapy for an extended period until the anti-Aβ antibody levels drop naturally as the effect of the vaccine decays over time. Obviously, improvements in vaccine design are needed to improve both the safety, as well as the efficacy of anti-Aβ immunotherapy. The focus of this review is on the advantages of DNA vaccination for anti-Aβ immunotherapy, and the major hurdles, such as immunosenescence, selection of appropriate molecular adjuvants, universal T cell epitopes, and possibly a polyepitope design based on utilizing existing memory T cells in the general population that were generated in response to childhood or seasonal vaccines, as well as various infections. Ultimately, we believe that the further refinement of our AD DNA epitope vaccines, possibly combined with a prime boost regime will facilitate translation to human clinical trials in either very early AD, or preferably in preclinical stage individuals identified by validated AD biomarkers.

Diseases of polyglutamine expansion, Alzheimer's disease and Parkinson's disease are neurodegenerative diseases associated with insoluble protein aggregates and neuronal death. These diseases constitute a group of devastating diseases for which there is currently little treatment. The protein aggregates may be the cause of neuronal death, although there is some controversy as to which form of aggregation (oligomers, polymers or microscopic aggregates) is the most toxic. More than a decade ago, the participation of transglutaminases in the formation of the abnormal protein aggregates was proposed. Transglutaminases are a large family of enzymes that catalyze the formation of Nε(γ-glutamyl)-lysine isodipeptide crosslinks between proteins. In this review, we summarize the evidence supporting the participation of transglutaminase in diseases of the central nervous system. We also describe newly developed transglutaminase inhibitors and their potential use as therapeutic agents in neurological disease.

Parkinson's disease (PD) is a type of motor system disorder that results from the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra (SN) of the midbrain. It is one of the most common neurodegenerative disorders, with an incidence that is second only to Alzheimer's disease (AD). Although replacement of dopamine can temporarily alleviate the symptoms of PD patients, it can not prevent the progression of the disease. Increasing evidence has suggested that neuroinflammation significantly contributes to the progress of PD. Therefore, anti-inflammatory therapy could represent a promising neuroprotective intervention with the potential to delay or prevent onset of the disease. This review summarizes several novel potential agents/candidates that might open new avenues for the treatment of PD. In addition to possessing demonstrated anti-inflammatory activities that operate through different molecular mechanisms, these agents exert neuroprotective effects by enhancing the production of neurotrophic factors or interfering with the apoptosis of neurons.

Cognitive deficits in patients with schizophrenia are the biggest obstacle to achieving an independent and productive lifestyle, with these deficits being refractory to current drug treatments. Significantly, both nicotinic and muscarinic receptors (cholinoceptors) have been shown to have an important role in cognition and are therefore viewed as potential therapeutic targets for drugs designed to lessen cognitive deficits. Importantly, the demonstration that acetylcholinesterase inhibitors, which result in higher synaptic levels of acetylcholine, can reduce the cognitive deficits of schizophrenia suggested that under-stimulation of cholinoceptors could be associated with the cognitive deficits associated with this disorder. This has lead to a focus on the development of receptor agonists, partial agonists and allosteric agonists that can be used to stimulate cholinergic pathways and thus reduce the cognitive deficits of schizophrenia. In addition, muscarinic receptors have now been associated with the modulation of dopamine and may constitute an alternative target for the treatment of psychoses. Given these exciting new therapeutic initiatives, this review will outline current evidence that involves the cholinoceptors in the pathophysiology of schizophrenia and how these data can inform on approaches to more targeted treatments for the disorder.