Mesenchymal stem cells (MSCs) exhibit immune-suppressive properties, follow a pattern of multilineage differentiation, and exhibit transdifferentiation potential. Ease in expansion from adult bone marrow, as well as its separation from ethical issues, makes MSCs appealing for clinical application. MSCs treated with retinoic acid resulted in synaptic transmission, based on immunostaining of synaptophysin and electrophysiological studies. In situ hybridization indicated that the neurotransmitter gene preprotachykinin-I was expressed in these cells. However, translation of this gene only occurred after stimulation with interleukin (IL)-1α. This effect was blunted by costimulation with IL-1 receptor antagonist. This study reports on the ability of MSCs to be transdifferentiated into neurons with functional synapses with the potential to become polarized towards producing specific neurotransmitters. Stem Cells 2005;23:383-391

GABA-mediated postsynaptic currents (IPSCs) were recorded from dopaminergic (DA) neurons of the ventral tegmental area (VTA) of rats, in acute brain slices, and from enzymatically or mechanically dissociated neurons. In young rats (3-10 d of age), where GABA is excitatory, glycine (1-3 M) and taurine (10 -30 M) increased the amplitude of evoked IPSCs (eIPSCs) and the frequency of spontaneous IPSCs (sIPSCs) but had minimal postsynaptic effects. Strychnine (1 M) blocked the action of glycine; when applied alone, it reduced the amplitude of eIPSCs and the frequency of sIPSCs, indicating a tonic facilitation of GABAergic excitation by some endogenous glycine agonist(s). In medium containing no Ca 2ϩ , or with Cd 2ϩ or tetrodotoxin added, the amplitude and especially the frequency of sIPSCs greatly diminished. In many cells, glycine had no effect on remaining miniature IPSCs, suggesting a preterminal site of glycine receptors (GlyRs). Fura-2 fluorescent imaging showed a glycine-induced increase of [Ca 2ϩ ] in nerve terminals (on DA neurons), which was suppressed by strychnine or 3 M -conotoxin MVIIA. Therefore, the presynaptic GlyR-mediated facilitation of GABAergic transmission seems to be mediated by N-and/or P/Q-type Ca 2ϩ channels. In older rats (22-30 d of age), where GABA causes inhibition, the effect of strychnine on GABAergic IPSCs was reversed to facilitation, indicating a tonic glycinergic inhibition of GABA release. Furthermore, glycine (1-3 M) reduced the amplitude of eIPSCs and the frequency of sIPSCs. Hence, the overall effect of the presynaptic action of glycine is to enhance the firing of DA cells, both in very young and older rats.

The generation of dopamine (DA) neurons from stem cells holds great promise in the treatment of Parkinson’s disease and other neural disease associated with dysfunction of DA neurons. Mesenchymal stem cells (MSCs) derived from the adult bone marrow show plasticity with regards to generating cells of other germ layers. In addition to reduced ethical concerns, MSCs could be transplanted across allogeneic barriers, making them desirable stem cells for clinical applications. We have reported on the generation of DA cells from human MSCs using sonic hedgehog (SHH), fibroblast growth factor 8 and basic fibroblast growth factor. Despite the secretion of DA, the cells did not show evidence of functional neurons, and were therefore designated DA progenitors. Here, we report on the role of brain‐derived neurotrophic factor (BDNF) in the maturation of the MSC‐derived DA progenitors. 9‐day induced MSCs show significant tropomyosin‐receptor‐kinase B expression, which correlate with its ligand, BDNF, being able to induce functional maturation. The latter was based on Ca2+ imaging analyses and electrophysiology. BDNF‐treated cells showed the following: increases in intracellular Ca2+ upon depolarization and after stimulation with the neurotransmitters acetylcholine and GABA and, post‐synaptic currents by electrophysiological analyses. In addition, BDNF induced increased DA release upon depolarization. Taken together, these results demonstrate the crucial role for BDNF in the functional maturation of MSC‐derived DA progenitors.

Ondansetron is a selective 5-hydroxytryptamine 3 (5-HT 3 ) receptor antagonist that has been introduced to clinical practice as an antiemetic for cancer treatment-induced and anesthesia-related nausea and vomiting. Its use under these circumstances is both prophylactic and therapeutic. It has a superior efficacy, safety and pharmacoeconomic profile compared with other groups of antiemetics, namely antidopaminergics, antihistamines and anticholinergics. However, its place in the management of anticipatory and delayed vomiting in cancer treatment and as a rescue antiemetic in surgical patients needs to be further explored. Furthermore, recent animal and human research also reflects its possible novel application in the treatment of other disease states, such as alcoholism, cocaine addiction, opioid withdrawal syndrome, anxiety disorders, gastrointestinal motility disorders, Tourette's syndrome and pruritus. This review revisits the widespread physiological and pathological effects of 5-HT and discusses both the basic science literature and the clinical developments responsible for the conventional and novel uses of ondansetron. In addition, new discoveries relating to the effects of ondansetron on other receptors/channels and their possible therapeutic applications are presented.

Mesenchymal stem cells (MSCs) are mesoderm-derived cells, primarily resident in adult bone marrow (BM). MSCs exhibit lineage differentiation to generate cells such as BM stroma, fat, and cartilage. Recent studies have reported the transdifferentiation of MSCs to cells of ectodermal and endodermal origin. Previously, we have reported transdifferentiation of human (h) MSCs into neuronal cells using retinoic acid (RA) as a differentiating agent. This study presents a more efficient induction method and rigorously characterizes the development using molecular, cellular, and functional approaches. A cocktail of induction agents containing basic fibroblast growth factor (bFGF) and RA generated cells that expressed glial and neuronal progenitor markers (GFAP) at day 2 post-induction. By day 12, 90% of hMSCs differentiated into cells that expressed markers consistent for neurons, including transcription factors linked to the development of differentiated neurons. Furthermore, cell proliferation studies and western blots for cell cycle-specific proteins demonstrated day-12 induced cells to be post-mitotic cells with no evidence of cell death. The cells exhibited spontaneous post-synaptic currents and were capable of neurotransmitter synthesis, packaging, and release. Together, the improved induction protocol, combined with an interdisciplinary approach to verify that hMSCs can differentiate into neuronal cells, provides a step toward translational application with models of regenerative medicine.