Current Drug Targets-CNS & Neurological Disorders - Volume 3, Issue 4, 2004

Accumulating evidence implicates inflammatory processes in the development of a number of neurodegenerative diseases and demonstrates that neurons and microglia can be a source for various cytokines, which are believed to be involved in neuropathology, and therefore can serve as targets for therapeutic treatment. Moreover, it is now established that many of these pro-inflammatory molecules, commonly associated with the peripheral immune system, are also produced within the central nervous system (CNS). The term “;cytokine network”; has been widely used to describe cytokine biology in the brain. However, the function of this network has not been well-characterised. It is believed that understanding the function of this network might have important clinical applications. This article reviews recent and current developments in cytokine research that pertain to the development of new strategies targeting cytokines in the brain, thus opening up new avenues for novel therapeutic approaches for the treatment of various pathological conditions and diseases of the CNS.

Based on epidemiological and observational studies, estrogen and hormone-replacement therapy were until recently viewed as major factors in the prevention of Alzheimer's disease (AD). However, a recent randomized clinical trial revealed that hormone replacement therapy using estrogen plus progestin may actually exacerbate the incidence of dementia when administered to elderly women. These contradictory reports have cast grave doubt on the role of estrogen in disease pathogenesis and led us to consider an alternate hypothesis that would be consistent with both observations. Specifically, we suspect that hormones of the hypothalamic pituitary gonadal axis such as gonadotropins, that are regulated by estrogen (or in males by testosterone), are involved in the pathogenesis of Alzheimer's disease. One such gonadotropin, luteinizing hormone (LH), is significantly elevated in both the sera and brain tissue of patients with AD and leads to an increased production of amyloid-β. Importantly, a key role in disease pathogenesis is further supported by the fact that the distribution of neuronal receptors for LH parallels those populations of neurons that degenerate during the course of the disease. That gonadotropins, not estrogen nor testosterone, mediate disease pathogenesis has led to a paradigm shift, not only for the treatment of AD but a wide variety of other age-related diseases. Therefore, the effects of agents that abolish LH, such as leuprolide acetate, which are currently being evaluated in Phase II clinical trials for the treatment of AD, are eagerly anticipated.

Mechanically sensitive ion channels (MSCs) are ubiquitous. They exist as two major types: those in specialized receptors that require fibrous proteins to transmit forces to the channel, and those in nonspecialized tissues that respond to stress in the lipid bilayer. While few MSCs have been cloned, the existing structures show no sequence or structural homology - an example of convergent evolution. The physiological function of MSCs in many tissues is not known, but they probably arose from the need for cell volume regulation. Recently, a peptide called GsMTx4 was isolated from tarantula venom and is the first specific reagent for mechanosensitive channels. GsMTx4 is a ∼ 4kD peptide with a hydrophobic face opposite a positively charged face. It is active in the D and L forms, and appears non-toxic to mice. GsMTx4 has shown physiological effects on cationic MSCs in heart, smooth muscle, astrocytes, and skeletal muscle. By itself, GsMTx4 can serve as a lead compound or as a potential drug. Its availability opens clinical horizons in the diagnosis and treatment of pathologies including cardiac arrhythmia, muscular dystrophy and glioma.

Neuron viability and defense against neurodegenerative disease can be achieved by targeting mitochondrial function to reduce oxidative stress, increase mitochondrial defense mechanisms, or promote energetic metabolism and Ca2+ homeostasis. Exposure to estrogen prior to contact with toxic agents can protect neurons against a wide range of degenerative insults. The proactive defense state induced by estrogen is mediated by complex mechanisms ranging from chemical to biochemical to genomic but which converge upon regulation of mitochondria function. Estrogen preserves ATP levels via increased / enhanced oxidative phosphorylation and reduced ATPase activity thereby increasing mitochondrial respiration efficiency, resulting in a lower oxidative load. In addition, estrogen increases antiapoptotic proteins, Bcl-2 and Bcl-xL, which prevents activation of the permeability transition pore protecting against estrogen-induced increase in mitochondrial Ca2+ sequestration. These effects are likely to be enhanced by antioxidant effects of estrogen, preventing the initiation of the deleterious “mitochondrial spiral”. The extent to which each of these mechanisms contribute to the overall proactive defense state induced by estrogen remains to be determined. However, each aspect of the cascade appears to make a significant if not obligatory impact on the neuroprotective effects of estrogens. Moreover each component of the cascade is required for estrogen regulation of mitochondrial function. Mechanisms of estrogen action and results of the clinical efficacy of estrogen therapy for prevention or treatment of Alzheimer's disease are considered in the context of clinical use of estrogen therapy and the design of brain selective estrogens or NeuroSERMs.

Perinatal stroke represents an important cause of severe neurological deficits that span the individual's lifetime, including delayed mental and motor development, epilepsy and major cognitive deficits. Most strokes occurring in term births, infants and children can be caused by thromboembolism from intracranial and extracranial vessels and are associated with a variety of risk factors such as birth asphyxia, cardiac diseases, blood disorders, maternal disorders, trauma. Animal models of perinatal stroke have been developed to examine the nature and the time course of the events occurring after the ischemic insult and the possible therapeutic strategies useful in reducing ischemic damage. The present article addresses the potential pharmacological treatments targeting the inflammatory process and apoptotic cell death, with a specific emphasis on the emerging role of statins as neuroprotective agents in perinatal stroke. As a prelude, we will also review advances in our understanding on the mechanisms underlying the hypoxic-ischemic reperfusion injury in the newborn.

The c-Jun N-terminal kinases (JNKs) are also called stress activated protein kinases (SAPKs) and are members of the family of mitogen activated protein kinases (MAPKs). While the functions of the JNKs under physiological conditions are diverse and not completely understood, there is increasing evidence that JNKs are potent effectors of apoptosis of oxidative stress-damaged cells in both the brain and the mammalian inner ear following a trauma. The activation of the inducible transcription factor c-Jun by N-terminal phosphorylation is a central event in JNK-mediated apoptosis of oxidative stress-damaged auditory hair cells following exposure to either acoustic trauma or a toxic level of an aminoglycoside antibiotic and also the apoptosis of auditory neurons as a consequence of a loss of the trophic support provided by the auditory hair cells. In this review, we summarise what is known about the expression and activation of G-proteins, JNKs, c-Jun and c-Fos under oxidative stress conditions within the mammalian cochlea. A particular focus is put on a new peptide conjugate that is a promising protective agent(s) and pharmacological strategies for preventing cochlear damage induced by both acoustic trauma and aminoglycoside ototoxic damage.

Along with inflammation, apoptosis appears a common feature of cell death in non-infectious neurodegenerative diseases. The apoptotic program is an energy-requiring, slowly developing process that evolves in three main steps; initiation, progression and execution. Each step of the program is controlled by a number of molecules with synergistic or antagonistic functions, among which the family of cystein proteases called caspases has a primary role. The central position of caspases in all steps of the apoptotic process had led to the development of several families of inhibitory drugs based on the tetrapeptidic sequence of their preferred cleavage site on target molecules. The initial classes of compounds had problems of toxicity, specificity and blood brain barrier penetration, but even so, gave encouraging preclinical results in animal models of neurological diseases. New generations of anti-caspase drugs have been developed, including non peptide-based compounds, which have shown satisfactory pharmaceutical activity. In addition, pre-clinical developments include advances in protein therapy based on the use of natural inhibitors of caspases, which possess the advantage of targeting synergistic neuroprotective pathways. This strategy uses peptidic vectors to carry large molecules through the blood brain barrier and the membrane of brain cells. Although pre-clinical data are compelling, the activity of these various drug families in patients with acute and / or progressive brain lesions has yet to be demonstrated.