Current Drug Targets-CNS & Neurological Disorders - Volume 2, Issue 6, 2003

There is a significant unmet need for therapeutic agents in the treatment of neurodegenerative diseases. Given their clinical importance, prototypical molecules that clearly exhibit both neuroprotective and neuroregenerative activities have been highly sought after. The journey led to the exploitation of neurotrophins, a family of proteins that had extraordinary therapeutic properties in pre-clinical models of neurodegeneration. Although experimentally promising, clinical development of neurotrophins for various neurological indications, such as Alzheimer's Disease, Amyotrophic Lateral Sclerosis, and Parkinson's Disease was met with severe obstacles and setbacks, such as the inability to deliver these large proteins to target population of neurons, instability of the proteins, and non-specific activity. Immunophilins are proteins that act as receptors for immunosuppresant drugs, i.e. FK506 (tacrolimus), cyclosporin A, and rapamycin (sirolimus, Rapamune). Studies indicate immunophilins are expressed 10-100 fold higher in CNS and PNS tissue than in immune tissue. Subsequent studies revealed potent neuroprotective and neuroregenerative properties of immunophilin ligands in both culture and animal models. In contrast to neurotrophins, most immunophilin ligands are highly stable, small molecules that can readily cross the blood-brain barrier and are orally bioavailable. Taken together, these data prompted the development of nonimmunosuppressive immunophilin ligands with potent therapeutic activities, although the potency of select compounds has come into question in more recent studies. This review will examine the experimental evidence supporting the use of immunophilin ligands for the treatment of neurodegenerative diseases and the current progression of these molecules in clinical trials.

Genomic research has produced an abundance of new candidate targets that remain to be validated as potential treatments for neuropsychiatric disorders. Functional neuroimaging, meanwhile, has provided detailed new insights into the neural circuits involved in emotional and cognitive control. At the growing interface between these independent lines of progress, new efforts are underway to unify our understanding of regional brain function with that of genetic and biochemical influences on behavior. Such a unified understanding of the mechanisms involved in cognitive and emotional control may open up new avenues for therapeutic intervention at the pharmacological and behavioral levels. In line with this, a new initiative sponsored by the National Institutes of Mental Health (NIMH) aims to bridge gaps between clinical diagnostics and the molecular processes that influence susceptibility to psychiatric disorders [1]. A major goal of this initiative is to identify the neural and neurochemical substrates of basic cognitive processes that are disrupted in psychiatric disorders and to examine the influence of genetic factors at the cognitive level. This review describes some well-known findings that are at the forefront of this interface. The progress already made indicates that the goals of the new initiative are well founded and achievable.

Classical medications employed to treat depression comprise mostly tricyclic antidepressants (TCAs), specific serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs), in accord with the recognized involvement of serotonergic and adrenergic systems in depression. Other therapies such as electro -convulsive shock, lithium intake and psychotherapy work via as yet unknown mechanisms. Although GABAergic neurotransmitter systems have not been central to etiological hypotheses for depression, observations are accumulating to suggest that these systems might play an important role in the induction of the disease. Lines of evidence in this regard include interactions between GABAergic and other neurotransmitter systems in depression, GABA levels in patients before and after antidepressant treatments, GABA levels and up / down regulations of GABA receptors in animal models of induced depression, and clinical effects of GABA receptor ligands. Phytomedicines that have a long history of useful applications are drawing increasing attention in pharmaceutical research. Moreover, while drug development is usually focused on single constituent drugs on account of their more accurately predictable physiological responses, complex herbal formulae represent an increasingly important source of drug discovery given the advent of high-throughput screening and specific receptor binding assays. Their active constituents acting on different neurotransmitter systems could be identified, and their therapeutic efficacies tested rigorously. Along with new insights into the underlying mechanisms of depression, the rich abundance of chemical entities from herbs is becoming an inviting resource in the search for effective treatment. This review addresses recent research on the possible role of GABAergic receptors with regard to depression, and potentially antidepressant phytomedicines acting on this class of receptors.

Cyclin-dependent kinase 5 (Cdk5), a Ser / Thr kinase, regulates the phosphorylation of neuronal proteins and thereby influences neuronal morphology, migration and axon growth. Tightly coordinated interactions between Cdk5 and its activator proteins p35 and p39 are critical for the developmental processes of postmitotic neurons as well as functioning of the adult CNS. Excessive up-regulation of Cdk5 activity leading to hyperphosphorylation of cytoskeletal proteins has been linked to neurodegenerative disorders, such as Alzheimer's disease (AD). On this basis it was proposed that Cdk5 might be a promising drug target. The physiologic role of Cdk5 in the adult CNS has been addressed recently. It was demonstrated that Cdk5 is involved in striatal and hippocampal neuronal plasticity and long-term behavioral changes associated with these processes. On the basis of the newly identified role of Cdk5 in synaptic plasticity, learning and memory the view that Cdk5 represents a good drug target in AD accompanied by cognitive dysfunctions may have to be revisited. Alternatively, targeting the mechanisms up-stream of Cdk5 leading to deregulation of Cdk5 activity, such as proteolytic cleavage of its activating subunits may prove to be more beneficial as a therapeutical approach.

Anxiety disorders are the most common psychiatric illness affecting both adults and children. Following the observation that m-chlorophenylpiperazine(mCPP) induced anxiety-like states in patients and in animal models, it was shown that in man, mCPP behaves as a functionally selective agonist at the 5-hydroxytryptamine (5-HT)2C receptor. This caused much interest in the development of antagonists at the 5-HT2C receptor for the treatment of anxiety disorders. This review examines the pre-clinical and clinical evidence for a role of the 5-HT2C receptor in anxiety and evaluates the progress of compounds that target this therapeutic approach.

This review will consider studies concerning the effects of cannabinoid receptor agonists and antagonists on memory in laboratory animals. Two subtypes of cannabinoid receptors have been identified to date; the central CB1 subtype and the peripheral CB2 subtype. The receptor which specifically binds Δ9-tetrahydrocannabinol (Δ9-THC) and related compounds in rat and human brain has been discovered and cloned by a number of researchers. This cannabinoid receptor is localized with high concentrations in different brain areas, including hippocampus and amygdala, which play an important role in the modulation of memory. In recent years evidence has been obtained that cannabinoids influence memory processes. It has been shown, for example, that Δ9-THC impairs memory in rats, mice and monkeys tested in a variety of experimental conditions (radial maze, instrumental discrimination tasks, Morris water maze, etc.). In some of these researches the effect of Δ9-THC was antagonized by the CB1 receptor antagonist SR 141716A, showing the involvement of this subtype of cannabinoid receptor in its effect. Anandamide, arachidonylethanolamide, was recently discovered as the first endogenous ligand for the cannabinoid receptor. It has been reported to stimulate CB1 receptors and to mimic the pharmacological effects of cannabinoids. Experiments carried out by our group have shown that anandamide impairs memory consolidation in random bred mice (CD1), exerts genotype-dependent influences on memory in inbred strain of mice (C57 BL / 6 and DBA / 2), and that opioid and dopaminergic systems might be involved in its effects.

ATP is a potent signaling molecule abundantly present in the CNS. It elicits a wide array of physiological effects and is regarded as the phylogenetically most ancient epigenetic factor playing crucial biological roles in several different tissues. These can range from neurotransmission, smooth muscle contraction, chemosensory signaling, secretion and vasodilatation, to more complex phenomena such as immune responses, pain, male reproduction, fertilization and embryonic development. ATP is released into the extracellular space either exocytotically or from damaged and dying cells. It is often co-released with other neurotransmitters and it can interact with growth factors at both receptor- and / or signal transduction-level. Once in the extracellular environment, ATP binds to specific receptors termed P2. Based on pharmacological profiles, on selectivity of coupling to second-messenger pathways and on molecular cloning, two main subclasses with multiple subtypes have been distinguished. They are P2X, i.e. fast cation-selective receptor channels (Na+, K+, Ca2+), possessing low affinity for ATP and responsible for fast excitatory neurotransmission, and P2Y, i.e. slow G protein-coupled metabotropic receptors, possessing higher affinity for the ligand. In the nervous system, they are broadly expressed in both neurons and glial cells and can mediate dual effects: short-term such as neurotransmission, and long-term such as trophic actions. Since massive extracellular release of ATP often occurs after metabolic stress, brain ischemia and trauma, purinergic mechanisms are also correlated to and involved in the etiopathology of many neurodegenerative conditions. Furthermore, extracellular ATP per se is toxic for primary neuronal dissociated and organotypic CNS cultures from cortex, striatum and cerebellum and P2 receptors can mediate and aggravate hypoxic signaling in many CNS neurons. Conversely, several P2 receptor antagonists abolish the cell death fate of primary neuronal cultures exposed to excessive glutamate, serum / potassium deprivation, hypoglycemia and chemical hypoxia. In parallel with these detrimental effects, also trophic functions have been extensively described for extracellular purines (both for neuronal and non-neuronal cells), but these might either aggravate or ameliorate the normal cellular conditions. In summary, extracellular ATP plays a very complex role not only in the repair, remodeling and survival occurring in the nervous system, but even in cell death and this can occur either after normal developmental conditions, after injury, or acute and chronic diseases.

Angiotensin II was initially described as a hormone of peripheral origin, the active end product of the Renin-Angiotensin System. The subsequent discovery that Angiotensin II was locally formed and selectively regulated in most organs indicated that tissue Angiotensin II systems might play additional important roles. After initial controversy, the presence of an Angiotensin II system in the brain is now universally accepted. Brain Angiotensin II is probably involved in the regulation of many brain functions. Angiotensin II AT1 receptors are localized not only in areas related to the regulation of autonomic and endocrine control, but also in many other areas of the brain involved in emotional, sensory and motor functions. Angiotensin II AT2 receptors are more abundant in brain areas related to sensory and motor control. The roles of brain Angiotensin II appear to be multiple and complex. In addition to a regulatory role in the control of the autonomic and hormone systems, the peptide participates in brain development, sensory processes, cognition and in the regulation of cerebrovascular flow. Recent developments indicate that blockade of the brain Angiotensin II AT1 receptors not only contributes to a significant blood pressure decrease in hypertension, but that simultaneous antagonism of peripheral and brain AT1 receptors reduces the sympathoadrenal and hormonal responses to stress and prevents stress-induced gastric injury. A novel role emerges for the use of peripheral and centrally acting AT1 receptor antagonists as therapeutically advantageous for the treatment of stress-related disorders.