Current Molecular Pharmacology - Volume 3, Issue 1, 2010

Neuronal dendrites are generated during development by a series of processes involving extension and retraction of dendritic branches in a first step, and subsequently stabilisation of existing dendrites through building of synaptic connections. These processes are tightly controlled at any of these time points and control of dendritic development follows individual differentiation stages. This review describes aspects of the maturation process in cerebellar Purkinje cells and spinal motoneurons. Although motoneurons are glutamatergic whereas Purkinje cells are GABAergic and thereby functionally very different, dendritic maturation processes appear to share common mechanisms and processes in both neuronal cell types. Genetically-regulated cell-intrinsic processes control dendritic outgrowth at an early stage, being thereafter supported by local growth factors. In contrast, increasing synaptic input promotes dendritic maturation by limiting overgrowth at a later stage, with Ca2+-dependent signalling involving PKC or CaMKII as the common mode of action. This series of events apparently is common for other neuronal cell types suggesting a generalised concept for intercellular control of neuronal connectivity.

Brain derived neurotrophic factor (BDNF), a member of the neurotrophin family of structurally related proteins that promote neuronal differentiation and survival during development [1, 2], is a potent modulator of synaptic plasticity [3-7]. Changes in BDNF expression, release and neuromodulatory activity, mediated by both epigenetic and posttranslational mechanisms, have been associated with many pathological conditions and developmental experiences, such as maternal deprivation and environmental enrichment. Much effort has been devoted to studying plasticity in the hippocampus, a structure traditionally associated with learning and memory, yet there is increasing empirical support for the contribution of another structure—the amygdala—to BDNF-induced changes. Because the amygdala is a critical site for emotional memory formation, and many emotional and neurodevelopmental pathologies have been linked to amygdalabased abnormalities, considerable efforts have been devoted to the characterization of its circuitry [8-11]. Here we review the role of BDNF as a biochemical integrator of convergent cellular signals, and as a central driver of neural plasticity . We conclude by emphasizing the importance of characterizing BDNF signaling cascades in behaviorally-relevant networks, to identify potential drug targets for novel therapeutic interventions.

The Kv currents are divided into three different K+ currents, such as slow inactivating transient K+ current (ID), fast inactivating transient K+ current (IA) and dominant sustained K+ current (IK), in small-diameter rat trigeminal ganglion (TG) neurons. The concentration of α-DTX (an ID blocker) to evoke the maximal inhibition of IA was 0.1 μM, and this concentration caused a 20 % inhibition of IA and increased the number of action potentials. Irrespective of the presence of 0.1 μM α-DTX, the application of 0.5 mM 4-AP (an IA blocker) caused a 51 % inhibition of IA and increased the number of action potentials. The responses were associated with the decreases in the resting membrane potential (RMP) and duration of depolarization phase of action potential (DDP). The application of 2 mM tetraethylammonium (TEA, an IK blocker) produced a 55 % inhibition of IK. Irrespective of the presence of both ID and IA blockers, the IK was the predominant K+ current. The prolongation of duration of action potential was usually observed following TEA treatment, suggesting that IA and IK had independent effects regulating the intrinsic firing properties of the action potential number and timing, respectively. Furthermore, the response characteristics of action potentials in the presence of both 4-AP and TEA resemble those of TG neurons in rats following chronic constriction nerve injury of the infraorbital nerve as well as after inferior alveolar nerve section. Thus, reducing effects of both IA and IK may be useful to investigate the mechanism of allodynia.

Glioblastoma, GBM, is the most frequent brain malignancy in adults. Patients with these tumors survive only, approximately, one year after diagnosis and rarely survive beyond two years. This poor prognosis is, in part, due to our insufficient understanding of the complex aggressive nature of these tumors and the lack of effective therapy. In GBM, over-expression of EGFR and/or its constitutively activated variant EGFRvIII is a major characteristic and is associated with tumorigenesis and more aggressive phenotypes, such as, invasiveness and therapeutic resistance. Consequently, both have been major targets for GBM therapy, however, clinical trials of EGFR- and EGFRvIII-targeted therapies have yielded unsatisfactory results and the molecular basis for the poor results is still unclear. Thus, in this review, we will summarize results of recent clinical trials and recent advances made in the understanding of the EGFR/EGFRvIII pathways with a key focus on those associated with intrinsic resistance of GBM to EGFR-targeted therapy. For example, emerging evidence indicates an important role that PTEN plays in predicting GBM response to EGFR-targeted therapy. Aberrant Akt/mTOR pathway has been shown to contribute to the resistant phenotype. Also, several studies have reported that EGFR/EGFRvIII's cross-talk with the oncogenic transcription factor STAT3 and receptor tyrosine kinases (c-Met and PDGFR) potentially lead to GBM resistance to anti-EGFR therapy. Other emerging mechanisms, including one involving HMG-CoA reductase, will also be discussed in this mini-review. These recent findings have provided new insights into the highly complex and interactive nature of the EGFR pathway and generated rationales for novel combinational targeted therapies for these tumors.