Drug connectivity mapping and functional analysis reveal therapeutic small molecules that differentially modulate myelination.

Disruption or loss of oligodendrocytes (OLs) and myelin has devastating effects on CNS function and integrity, which occur in diverse neurological disorders, including Multiple Sclerosis (MS), Alzheimer's disease and neuropsychiatric disorders. Hence, there is a need to develop new therapies that promote oligodendrocyte regeneration and myelin repair. A promising approach is drug repurposing, but most agents have potentially contrasting biological actions depending on the cellular context and their dose-dependent effects on intracellular pathways. Here, we have used a combined systems biology and neurobiological approach to identify compounds that exert positive and negative effects on oligodendroglia, depending on concentration. Notably, next generation pharmacogenomic analysis identified the PI3K/Akt modulator LY294002 as the most highly ranked small molecule with both pro- and anti-oligodendroglial concentration-dependent effects. We validated these in silico findings using multidisciplinary approaches to reveal a profoundly bipartite effect of LY294002 on the generation of OPCs and their differentiation into myelinating oligodendrocytes in both postnatal and adult contexts. Finally, we employed transcriptional profiling and signalling pathway activity assays to determine cell-specific mechanisms of action of LY294002 on oligodendrocytes and resolve optimal in vivo conditions required to promote myelin repair. These results demonstrate the power of multidisciplinary strategies in determining the therapeutic potential of small molecules in neurodegenerative disorders.

Activity of some Mexican medicinal plant extracts on carrageenan-induced rat paw edema.

The extracts obtained from 14 plants of the Mexican medicinal flora were assessed for anti-inflammatory activity by carrageenan-induced rat paw edema model. The i.p. administration of the extracts at a dose of 400 mg/kg produced a high reduction of edema with 70% of the plant extracts. Oenothera rosea methanol extract, Sphaeralcea angustifolia chloroform extract, Acaciafarnesiana, Larrea tridentata and Rubus coriifolius methanol extracts as well as the aqueous extract of Chamaedora tepejilote were demonstrated to be particularly active against the induced hind-paw edema. Moderate inhibition of edema formation was also demonstrated with the methanol extracts of Astianthus viminalis, Brickellia paniculata, C. tepejilote and Justicia spicigera.

An experimental study of reflex variability in selective dorsal rhizotomy.

Significant problems regarding the measurement technique currently used to choose nerve roots for sectioning in the selective dorsal rhizotomy procedure have recently been reported. To better understand the source of these problems, a series of six experiments was performed in which the selective rhizotomy technique was applied to cats that were either intact, decerebrate, or spinalized. Measurements were made before and after partial rhizotomy. In decerebrate preparations, large, spontaneous changes in reflex threshold were observed over short periods of time, especially after partial rhizotomy was performed, and threshold changes greater than 1000% could be observed over 10-minute periods. Using constant-current stimulation of the dorsal root at threshold, the response of each ipsilateral leg muscle demonstrated frequent changes, and changes coincided with the variability in threshold estimation. In addition, very low thresholds were measured (0.1 to 0.25 mA) in half (3 of 6) of these experiments, these measurements being well below the currents customarily used for intraoperative decision making. Stimulation at twice threshold was found to consistently increase the pathological quality of the responses observed. Although intact animals never displayed contralateral responses when stimulated at threshold, such contralateral responses could readily be elicited at twice threshold. These laboratory results raise further doubts regarding the reliability of the measurement techniques now widely used for selective dorsal rhizotomy.