Current Medicinal Chemistry - Central Nervous System Agents - Volume 5, Issue 2, 2005

Monoamine transporters (MAT) are the target molecules of cocaine for induction of its central stimulating effect, resultant reward. Sensitization of central nervous system stimulation by cocaine is produced by intermittent use of cocaine and typically appears in behavioral hyperactivity in animals. Na+ channels are other important molecules for induction of seizures of cocaine in abuse. The mechanisms for the expression of seizures and development of cocaine kindling by repeated cocaine intake may include the facilitation by inhibition of MAT of seizures induced by γ-aminobutyric acid obstacle-related mechanism resulting from an inhibition of Na+ channels on the nerve by cocaine. Various molecular biological techniques have been utilized to investigate the structure-function relationship of MAT molecules and revealed multiple molecular determinates on MAT molecules for critical interaction with cocaine. The evidence would help to understand the molecular interaction of MAT and cocaine, leading to the development of medication for cocaine reward and kindling.

The pharmacological treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS) currently represents a major medical challenge. The mechanisms involved in the apoptotic neuronal cell death, associated with such disorders, are still not clear, but recent data suggest that cyclindependent kinases (CDKs) play a prominent role (Liu et al., 2003). Canonical CDKs such as CDK2 and CDK4/CDK6 are enzymes associated with cyclin regulatory subunits that control cell cycle progression. The evidence that neurons in postmortem brain tissue from patients with neurodegenerative diseases express CDKs, supports to the hypothesis that re-entry into the cell cycle could be an apoptotic pathway involved in the neurodegenerative process. Several authors suggest that the transcription factor E2F-1 function as a link between the cell cycle and apoptosis in neurons. Additionally the expression of CDK5 has been demonstrated in postmortem brain tissue from patients with neurodegenerative diseases. CDK5 is an atypical CDK, that does not require association with a cyclin and is not implicated in the cell cycle progression. Instead, it is associated with the neuronal co-activators p35 and p39, and is required for neuronal development, axonal outgrowth, learning and memory. Recent evidence also points to a leading role for CDK5/p25 in apoptosis and neurodegeneration. CDK inhibitors such as flavopiridol and roscovitine are being developed and tested in clinical trials as novel antineoplasic agents. Thus, due to the implication of CDKs in neuronal apoptosis, a new application of these drugs in the treatment of neurodegenerative diseases is suggested.

Alzheimer's disease (AD) is the most common form of neurodegenerative disease with dementia in the elderly. Besides the pathological hallmarks of the disease, which include cerebral deposits of amyloid-β (Aβ) peptides and neurofibrillary tangles, AD brain exhibits clear evidence of a chronic inflammatory process. Epidemiological studies have shown that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing and delays the onset of AD. Classical NSAIDs can target pathological pathways that have been involved in this disease, such as cycloxygenase (COX), nuclear factor k beta (NF-kB), peroxisome proliferator-activated receptors. However, recent studies indicate that a subset of NSAIDs such as ibuprofen, indomethacin and flurbiprofen also have direct Aβ-lowering properties in cell cultures as well as transgenic models of AD-like amyloidosis. Elucidation of these old and new pharmacological aspects will give us important clues for future clinical trials with these drugs. This article summarizes how some NSAIDs by combining anti-inflammatory and anti-amyloidogenic properties, could ultimately result in a novel therapeutic approach for AD treatment.

At least nine neurodegenerative diseases are caused by the expansion of a polyglutamine (polyQ) tract in the associated disease proteins. Although these proteins are normally expressed in either the cytoplasm or the nucleus, polyQ expansion can cause them to accumulate and aggregate in the nucleus. Moreover, addition of an expanded polyQ tract to a small cytoplasmic protein, hypoxanthine-guanine-phosphoribosyltransferase (HPRT), leads to its accumulation in neuronal nuclei and neurological symptoms in transgenic mice. There is growing evidence that proteins with expanded polyglutamine tracts can abnormally interact with transcription factors, resulting in transcriptional dysregulation and cellular toxicity. However, several critical issues remain unclear. One question is how mutant proteins with expanded polyQ readily accumulate in the nucleus. It is also largely unclear whether both soluble and aggregated polyQ disease proteins can affect gene expression and whether they act in the nucleus via a common mechanism. Understanding these issues will help the development of therapeutics for the polyQ diseases. We review recent literature regarding these issues and discuss potential strategies to prevent or attenuate transcriptional dysregulation caused by intranuclear polyQ disease proteins.

Injury to the peripheral nerve can lead to paradoxical changes in functioning such that there is an ongoing dysesthesia and an altered processing such that low threshold stimuli are responded to in humans and animals as if they were painful. What are the mechanisms underlying these anomalous behaviors? The biological changes induced by nerve injury are complex. To attribute functional relevance to the many changes, systematic preclinical work using well-defined behavioral models of nerve injury has been undertaken. Such studies have provided support for the important role in nerve injury-evoked pain behavior for a number of channels and receptors in the injured nerve, the dorsal root ganglion of the injured nerve, and the dorsal horn. These changes and their effect upon behavior are the subject of this review.

The ventral medullary surface of the medulla oblongata is known as the site of the central chemosensitive neurons in humans. These neurons sense decrease in pH of the cerebrospinal fluid followed by hypercapnia (increased arterial CO2) and induce hyperventilation. Recently, several advances have been made in understanding central chemosensitivity at the molecular and cellular levels. Recent studies have identified several transcription factors such as c-Jun, c-Fos, FosB and small Maf proteins that may play critical roles in the brain adaptation to hypercapnia. Hypercapnic stimulation also activates c-Jun NH2-terminal kinase (JNK) cascade via influx of extracellular Ca2+ through voltage-gated Ca2+ channels. In addition, several transmembrane proteins including Rhombex-29 (rhombencephalic expression protein-29 kDa) and Past-A (proton-associated sugar transporter-A) have been implicated in regulation of H+ sensitivity and brain acidosismediated energy metabolism, respectively. These novel discoveries may provide new insights into the design for new drugs and understanding of neurological disorders. This review focuses on the properties of genes stimulated by acidosis in response to hypercapnia and discusses current knowledge on the molecular basis of neuronal regulation during acidosis.

Activated innate immune response in brain has been extensively associated with several diseases, including Alzheimer's disease, HIV-associated dementia, ischemia, head trauma, stroke, cerebral palsy, axonal degeneration in multiple sclerosis, and autism. Although initially investigated because of its role innate immune response to microorganisms, the CD14/Toll-like receptor pathway is now appreciated as a critical element in innate immune response to endogenous ligands, including fibrillar amyloid β peptides and neoantigens expressed by apoptotic cells. Here we review data on NSAID suppression of cerebral oxidative damage, as measured by F2-isoprostanes, and synaptodendritic degeneration in an in vivo model of CD14-dependent activation of glial innate immune response. Given recent concern over toxicity from protracted exposure to NSAIDs, we also review data from mice lacking specific receptors for PGE2, and show that mice lacking EP2, but not EP1, are completely protected from CD14-dependent paracrine neurotoxicity. These results suggest that EP2 may be a new and more focused target in the PG pathway to suppress innate immunity-mediated neuronal damage.

It is well established that the neuroactive steroids can modulate neuronal activity in the peripheral and central nervous system causing a variety of behavioral and neuroendocrine changes in humans and animals. It is largely believed that their effects on neurosensory processing and neuronal excitability are primarily mediated by effects on various ligandgated ion channels, with much attention focused on the modulation of γ-aminobutyric acid (GABAA) receptors. However, some important behavioral effects of neuroactive steroids may be mediated by the family of voltage-gated calcium channels. Recent evidence strongly suggests that modulation of peripheral T-type calcium channels influences somatic and visceral nociceptive inputs and that inhibition of T currents results in significant anti-nociception in a variety of animal pain models. Therefore, T channels in peripheral nociceptors may be important, although previously unappreciated, targets for anti-nociceptive therapeutic agents including neuroactive steroids. Currently available pain therapies remain limited with inadequate efficacy and numerous side effects. Hence, the development of novel neuroactive steroids that are selective and potent blockers of neuronal T-type Ca2+ channels may greatly aid in revealing roles for these channels in sensory pathways (nociception in particular) and in the development of novel analgesics that might be safer and more effective for pain therapy. In the present review, we summarize the putative role of peripheral T-type calcium channels in nociception and our recent in vivo and in vitro structure-activity studies focusing primarily on 5β-reduced neuroactive steroids that are potent peripheral analgesics and potent blockers of neuronal T-type calcium channels.