Current Neuropharmacology - Volume 6, Issue 2, 2008

Protein aggregates or inclusion bodies are common hallmarks of age-related neurodegenerative disorders. Why these aggregates form remains unclear. Equally debated is whether they are toxic, protective, or simple by-products. Increasing evidence, however, supports the notion that in general aggregates confer toxicity and disturb neuronal function by hampering axonal transport, synaptic integrity, transcriptional regulation, and mitochondrial function. Thus, neuroscientists in search of effective treatments to slow neural loss during neurodegeneration have long been interested in finding new ways to clear inclusion bodies. Intriguingly, two studies using conditional neuron-specific gene ablations of autophagy regulators in mice revealed that autophagy loss elicits inclusion body formation and a neurodegenerative cascade. Such studies indicate autophagy may be a built-in defense mechanism to clear the nervous system of inclusion bodies. This new finding has implications for our understanding of aging and neurodegeneration and the development of new therapies. First, we discuss the pathways underlying autophagy and its controversial role in cell death and survival regulation. We then discuss the physiological role of autophagy in the aging process of the nervous system. In the final portion of this review, we discuss the therapeutic promise of inducing autophagy and the potential side effects of such treatments.

Programmed cell death (PCD), is a highly regulated and sophisticated cellular mechanism that commits cell to isolated death fate. PCD has been implicated in the pathogenesis of numerous neurodegenerative disorders. Countless molecular events underlie this phenomenon, with each playing a crucial role in death commitment. A precedent event, apoptotic volume decrease (AVD), is ubiquitously observed in various forms of PCD induced by different cellular insults. Under physiological conditions, cells when subjected to osmotic fluctuations will undergo regulatory volume increase/ decrease (RVI/RVD) to achieve homeostatic balance with neurons in the brain being additionally protected by the blood-brain-barrier. However, during AVD following apoptotic trigger, cell undergoes anistonic shrinkage that involves the loss of water and ions, particularly monovalent ions e.g. K+, Na+ and Cl-. It is worthwhile to concentrate on the molecular implications underlying the loss of these cellular components which posed to be significant and crucial in the successful propagation of the apoptotic signals. Microarray and real-time PCR analyses demonstrated several ion and water channel genes are regulated upon the onset of lactacystin (a proteosomal inhibitor)-mediated apoptosis. A time course study revealed that gene expressions of water and ion channels are being modulated just prior to apoptosis, some of which are aquaporin 4 and 9, potassium channels and chloride channels. In this review, we shall looked into the molecular protein machineries involved in the execution of AVD in the central nervous system (CNS), and focus on the significance of movements of each cellular component in affecting PCD commitment, thus provide some pharmacological advantages in the global apoptotic cell death.

Behavioral and psychological symptoms of dementia (BPSD), i.e. verbal and physical aggression, agitation, psychotic symptoms (hallucinations and delusions), sleep disturbances, oppositional behavior, and wandering, are a common and potentially severe problem complicating dementia. Their prevalence is very high and it is estimated that up to 90% of patients with Alzheimer's disease (AD) may present at least one BPSD. Beside the obvious impact on the quality of life of people with dementia, BPSD are responsible for increased risk of patient institutionalization and increased costs. Furthermore, they are associated with caregivers' stress and depression. Drugs used include antipsychotics, antidepressants, anticonvulsivants, anxiolytics, cholinesterase inhibitors and N-methyl-D-aspartate receptor modulators. Among these, the most commonly used are anti-psychotics. These drugs have been used for many decades, but in the last years new compounds have been marketed with the promise of comparable efficacy but less frequent adverse effects (especially extra-pyramidal side effects). Their safety, however, has been challenged by data showing a potential increase in adverse cerebrovascular side effects and mortality. This review will summarize the pathophysiology and neuropharmacology of BPSD, it will describe the characteristics of the anti-psychotics most commonly used focusing on their efficacy and safety in BPSD.

Most women using heroin are of reproductive age with major risks for their infants. We review clinical and experimental data on fetal, neonatal and postnatal complications associated with methadone, the current “gold standard”, and compare these with more recent, but limited, data on developmental effects of buprenorphine, and naltrexone. Methadone is a μ-opioid receptor agonist and is commonly recommended for treatment of opioid dependence during pregnancy. However, it has undesired outcomes including neonatal abstinence syndrome (NAS). Animal studies also indicate detrimental effects on growth, behaviour, neuroanatomy and biochemistry, and increased perinatal mortality. Buprenorphine is a partial μ-opioid receptor agonist and a κ-opioid receptor antagonist. Clinical observations suggest that buprenorphine during pregnancy is similar to methadone on developmental measures but is potentially superior in reducing the incidence and prognosis of NAS. However, small animal studies demonstrate that low doses of buprenorphine during pregnancy and lactation lead to changes in offspring behaviour, neuroanatomy and biochemistry. Naltrexone is a non-selective opioid receptor antagonist. Although data are limited, humans treated with oral or sustained-release implantable naltrexone suggest outcomes potentially superior to those with methadone or buprenorphine. However, animal studies using oral or injectable naltrexone have shown developmental changes following exposure during pregnancy and lactation, raising concerns about its use in humans. Animal studies using chronic exposure, equivalent to clinical depot formulations, are required to evaluate safety. While each treatment is likely to have maternal advantages and disadvantages, studies are urgently required to determine which is optimal for offspring in the short and long term.

Transient Receptor Potential Vanilloid 1 (TRPV1) is a Ca2+ permeant non-selective cation channel expressed in a subpopulation of primary afferent neurons. TRPV1 is activated by physical and chemical stimuli. It is critical for the detection of nociceptive and thermal inflammatory pain as revealed by the deletion of the TRPV1 gene. TRPV1 is distributed in the peripheral and central terminals of the sensory neurons and plays a role in initiating action potentials at the nerve terminals and modulating neurotransmitter release at the first sensory synapse, respectively. Distribution of TRPV1 in the nerve terminals innervating blood vessels and in parts of the CNS that are not subjected to temperature range that is required to activate TRPV1 suggests a role beyond a noxious thermal sensor. Presently, TRPV1 is being considered as a target for analgesics through evaluation of different antagonists. Here, we will discuss the distribution and the functions of TRPV1, potential use of its agonists and antagonists as analgesics and highlight the functions that are not related to nociceptive transmission that might lead to adverse effects.

Recent advances in our understanding of the mechanisms in the cascade of events resulting in retinal cell death in ocular pathologies like glaucoma, diabetic retinopathy and age-related macular degeneration led to the common descriptive term of neurodegenerative diseases of the retina. The final common pathophysiologic pathway of these diseases includes a particular form of metabolic stress, resulting in an insufficient supply of nutrients to the respective target structures (optic nerve head, retina). During metabolic stress, glutamate is released initiating the death of neurones containing ionotropic glutamate (N-methyl-D-aspartat, NMDA) receptors present on ganglion cells and a specific type of amacrine cells. Experimental studies demonstrate that several drugs reduce or prevent the death of retinal neurones deficient of nutrients. These agents generally block NMDA receptors to prevent the action of glutamate or halt the subsequent pathophysiologic cycle resulting in cell death. The major causes for cell death following activation of NMDA receptors are the influx of calcium and sodium into cells, the generation of free radicals linked to the formation of advanced glycation endproducts (AGEs) and/or advanced lipoxidation endproducts (ALEs) as well as defects in the mitochondrial respiratory chain. Substances preventing these cytotoxic events are considered to be potentially neuroprotective.