Current Neuropharmacology - Volume 3, Issue 4, 2005

Cell transplantation is a promising strategy for the treatment of neurodegenerative and muscle degenerative diseases. Many kinds of cells, including embryonic stem cells and tissue stem cells, have been considered as candidates for transplantation therapy. Bone marrow stromal cells (MSCs) have great potential as therapeutic agents since they are easy to isolate and can be expanded from patients without serious ethical or technical problems. We discovered a new method for the highly efficient and specific induction of functional Schwann cells, neurons and skeletal muscle lineage cells from both rat and human MSCs. These induced cells were transplanted into animal models of neurotraumatic injuries, Parkinson's disease, stroke and muscle dystrophies, resulting in the successful integration of transplanted cells and an improvement in behavior of the transplanted animals. Here we focus on the respective potentials of MSCderived cells and discuss the possibility of clinical application in degenerative diseases.

Although originally proposed as a subtype of opioid receptors, the sigma receptor is now confirmed to be a non-opioid receptor that binds diverse classes of psychotropic drugs. Sigma receptors are subdivided into two subtypes, sigma-1 and sigma-2. The sigma-1 receptor is a 25-kDa protein possessing one putative transmembrane domain and an endoplasmic reticulum retention signal. Sigma-1 receptors are highly expressed in deeper laminae of the cortex, olfactory bulb, nuclei of mesencephalon, hypothalamus, and Purkinje cells in the brain. Sigma-1 receptors are predominantly localized at the endoplasmic reticulum of both neurons and oligodendrocytes. From behavioral studies, sigma-1 receptors were shown to be involved in higher-ordered brain functions including memory and drug dependence. The actions mediated by sigma-1 receptors at the cellular level can be considered either as acute or chronic. The acute actions include the modulation of ion channels (i.e., K+ channel, NMDA receptors, IP3 receptors) and the sigma-1 receptor translocation. Chronic actions of sigma-1 receptors are basically considered to be the result of an up- or down regulation of the sigma-1 receptor itself. For example, the upregulation of sigma-1 receptors per se, even without exogenous ligands, promotes cellular differentiation and reconstitution of lipid microdomains (lipid rafts) in cultured cells. These findings together suggest that sigma-1 receptors might possess a constitutive biological activity, and that sigma-1 receptor ligands might merely work as modulators of the innate activity of this protein. Recent in vitro and in vivo studies strongly point to the possibility that sigma-1 receptors participate in membrane remodeling and cellular differentiation in the nervous system.

Long-term alcohol exposure gives rise to development of physical dependence on alcohol in consequence of changes in certain neurotransmitter functions. Accumulating evidence suggests that the glutamatergic neurotransmitter system, especially the N-methyl-D-aspartate (NMDA) type of glutamate receptors is a particularly important site of ethanol's action, since ethanol is a potent inhibitor of the NMDA receptors (NMDARs) and prolonged ethanol exposition leads to a compensatory "upregulation" of NMDAR mediated functions supposedly contributing to the occurrence of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal. Recently, expression of different types of NMDAR subunits was found altered after long-term ethanol exposure. Especially, the expression of the NR2B and certain splice variant forms of the NR1 subunits were increased in primary neuronal cultures treated intermittently with ethanol. Since NMDA ion channels with such an altered subunit composition have increased permeability for calcium ions, increased agonist sensitivity, and relatively slow closing kinetics, the abovementioned alterations may underlie the enhanced NMDAR activation observed after long-term ethanol exposure. In accordance with these changes, the inhibitory potential of NR2B subunit-selective NMDAR antagonists is also increased, demonstrating excellent potency against alcohol withdrawal-induced in vitro cytotoxicity. Although in vivo data are few with these compounds, according to the effectiveness of the classic NMDAR antagonists in attenuation, not only the physical symptoms,but also some affective and motivational components of alcohol withdrawal, novel NR2B subunit selective NMDAR antagonists may offer a preferable alternative in the pharmacotherapy of alcohol dependence.

Anticonvulsant and neuroprotective effects of agonist and antagonist of metabotropic glutamate receptors (mGluRs) have been known for more than 10 years from multiple studies. However, it is not certain whether these candidate drugs are also antiepileptic and antiepileptogenic, as few studies included the chronic stages to determine whether spontaneous recurrent seizures could be prevented or stopped. Even in the acute stage, differences in experimental design such as timing and route of administration of candidate drugs, age, species and strain of experimental animal and experimental model make it difficult to determine the anticonvulsant and neuroprotective effects of each candidate drug. This paper, reviews in vivo neuropharmacological studies on agonsists and antagonists of mGluRs in different seizure and epilepsy models in last more than ten years. By combining with our neuropharmacological studies on the effect of mGluR agonists and antagonists in the mouse pilocarpine model of temporal lobe epilepsy, an ideal model for future development of mGluR agonists and antagonists as antiepileptogenic drugs will be proposed.

Structure and function of the brain are use-dependent variables based on "synapse plasticity". Since synapses are driven by chemical transmitters, synaptic functions are liable to be modified by extrinsic chemicals displaying affinities for synaptic receptors or modulators. Caffeine is a widely used chemical substance that can invade synapses, and has several biochemical and metabolic actions on synaptic activities. This review focuses on the actions of caffeine on changes in structure and function in the region of the hippocampal formation and neocortex, which exhibit high synapse plasticity. At the synapse level, various synaptic receptors and channel activities are modulated by caffeine via mobilization of intracellular calcium, inhibition of phosphodiesterase, antagonism of adenosine receptors and GABA receptors. These actions of caffeine enable neurons to induce plastic changes in the properties of synaptic activities, such as synaptic transmission efficiency and morphology. At the network level, caffeine has the ability to activate cortical neural oscillators that deliver repetitive N-methyl-D-aspartate receptor-dependent signals to surrounding areas, causing strengthening of long-range inter-cortical communications. Caffeine might thus allow reorganization of cortical network functions via synaptic mobilizations.

Ischemic brain injury is implicated in the pathophysiology of stroke and brain trauma, which are among the top killers worldwide, and intensive studies have been performed to reduce neural cell death after cerebral ischemia. Alpha 2- adrenergic agonists have been shown to improve the histomorphological and neurological outcome after cerebral ischemic injury when administered during ischemia, and recent studies have provided considerable evidence that alpha 2-adrenergic agonists can protect the brain from ischemia/reperfusion injury. Thus, alpha 2-adrenergic agonists are promising potential drugs in preventing cerebral ischemic injury, but the mechanisms by which alpha 2-adrenergic agonists exert their neuroprotective effect are unclear. Activation of both the alpha 2-adrenergic receptor and imidazoline receptor may be involved. This mini review examines the recent progress in alpha 2-adrenergic agonists - induced neuroprotection and its proposed mechanisms in cerebral ischemic injury.