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In breast cancer it has been proposed that the presence of cancer stem cells may drive tumor initiation, progression and recurrences. IL-8, up-regulated in breast cancer, and associated with poor prognosis, increases CSC self-renewal in cell line models. It signals via two cell surface receptors, CXCR1 and CXCR2. Recently, the IL-8/CXCR1 axis was proposed as an attractive pathway for the design of specific therapies against breast cancer stem cells. Reparixin, a powerful CXCR1 inhibitor, was effective in reducing in vivo the tumour-initiating population in several NOD/SCID mice breast cancer models, showing that the selective targeting of CXCR1 and the combination of reparixin and docetaxel resulted in a concomitant reduction of the bulk tumour mass and CSC population. The available data indicate that IL-8, expressed by tumour cells and induced by chemotherapeutic treatment, is a key regulator of the survival and self-renewal of the population of CXCR1-expressing CSC. Consequently, this investigation on the mechanism of action of the reparixin/paclitaxel combination, was based on the observation that reparixin treatment contained the formation of metastases in several experimental models. However, specific data on the formation of breast cancer brain metastases, which carry remarkable morbidity and mortality to a substantial proportion of advanced breast cancer patients, have not been generated. The obtained data indicate a beneficial use of the drug combination reparixin and paclitaxel to counteract brain tumour metastasis due to CSC, probably due to the combined effects of the two drugs, the pro-apoptotic action of paclitaxel and the cytostatic and anti-migratory effects of reparixin.

Three macaque monkeys and 13 healthy human volunteers underwent diffusion tensor MRI with a 3 Tesla scanner for diffusion tract tracing (DTT) reconstruction of callosal bundles from different areas. In six macaque monkeys and three human subjects, the length of fiber tracts was obtained from histological data and combined with information on the distribution of axon diameter, so as to estimate callosal conduction delays from different areas. The results showed that in monkeys, the spectrum of tract lengths obtained with DTT closely matches that estimated from histological reconstruction of axons labeled with an anterogradely transported tracer. For each sector of the callosum, we obtained very similar conduction delays regardless of whether conduction distance was obtained from tractography or from histological analysis of labeled axons. This direct validation of DTT measurements by histological methods in monkeys was a prerequisite for the computation of the callosal conduction distances and delays in humans, which we had previously obtained by extrapolating the length of callosal axons from that of the monkey, proportionally to the brain volumes in the two species. For this analysis, we used the distribution of axon diameters from four different sectors of the corpus callosum. As in monkeys, in humans the shortest callosal conduction delays were those of motor, somatosensory, and premotor areas; the longer ones were those of temporal, parietal, and visual areas. These results provide the first histological validation of anatomical data about connection length in the primate brain based on DTT imaging.

Patients with Parkinson's disease show unbalanced capability to manage self-paced vs externally driven movements, or automatic-associated movements with respect to the intended voluntary movements. We studied the effect of a selective loss of dopaminergic terminals within the striatum and the execution of a well-learned set-shifting task as revealed using tyrosine hydroxylase immunoreactivity and magnetic resonance imaging in the rat. We found that, both in the externally cued condition, and in the externally-internally driven switching task, the cue-dependent constraints interfered with motor readiness in over training condition. The unilateral dopaminergic striatal depletion enhanced the switch-induced performance differences in favour of the internally-externally cued transition. Dopamine depleted rats, in fact, were impaired to produce an alternative motion when task switching required to change from an over trained behaviour, towards an alternative self-paced response. The comparative analysis of behavioural, tyrosine hydroxylase immunoreactivity and magnetic resonance imaging data, revealed a shrinkage of the lesioned striatum, and an enlargement of the ipsilateral ventricle that could provide useful markers for monitoring pathological changes occurring during early stages of Parkinson's disease in vivo., (Copyright © 2013 Elsevier B.V. All rights reserved.)

There is evidence that deep brain stimulation (DBS) of the pedunculopontine tegmental nucleus (PPTg) improves parkinsonian motor signs. The mechanisms that mediate these effects and the modifications that occur in the PPTg in Parkinson's disease (PD) are not fully known and are the object of current debate. The aim of this paper was to critically review available data with respect to (1) the presence of PPTg neurons linked to reticulospinal projections, (2) the involvement of these neurons in modulating spinal reflexes, and (3) the participation of fibers close to or within the PPTg region in such modulation. The PPTg neurons are distributed in a large pontotegmental region, stimulation of which can evoke activity in hindlimb, shoulder and neck muscles, and potentiate motor responses evoked by stimulation of dorsal roots. This influence seems to be carried out by fast-conducting descending fibers, which likely run in the medial reticulospinal pathway. It is yet unclear which neurotransmitters are involved and on which elements of the gray matter of the spinal cord PPTg fibers synapse. The modulation of spinal cord activity which can be achieved by stimulating the PPTg region seems to be mediated not only by PPTg neurons, but also by tecto-reticular fibers which run in the pontotegmental area, and which likely are activated during PPTg-DBS. The importance of these fibers is discussed taking into account the degeneration of PPTg neurons in PD and the benefits in gait and postural control that PPTg-DBS exerts in PD. The potential usefulness of PPTg-DBS in other neurodegenerative disorders characterized by neuronal loss in the brainstem is also considered.

Electrical stimulation of the rat pedunculopontine nucleus (PPTg) (<25 Hz) synchronized firing of subthalamic neurons (STN) with each stimulus, and a continuous irregular activity often preceded recovery of burst discharges in control as well as in 6-hydroxydopamine lesioned animals. Firing was blocked both by increasing frequency of stimulation (>50 Hz) and current intensity (>500 microA). The data suggest that clinically relevant frequencies for PPTg deep brain stimulation in Parkinson's disease modulate burst discharges in STN neurons.

Recent data suggest a potential role of pedunculopontine nucleus (PPN) electrical stimulation in improving gait and posture in Parkinson's disease. Because the PPN receives fibres from the subthalamic nucleus (STN), we investigated the effects of STN-high-frequency stimulation (HFS) on PPN neuronal activity in intact rats and in rats bearing either an ibotenate lesion of the entopeduncular nucleus (EP) or a lesion of the substantia nigra (SN). The main response of PPN neurons to STN single-shock stimulations in the three experimental groups was a short latency (4.5 +/- 2.1 ms) and brief (15.3 +/- 6.5 ms) excitation. This response was maintained during 1-5 s of STN-HFS (130 Hz, 60 micros, 100-1000 microA). In EP-lesioned rats the percentage (75.0%) of PPN neurons showing a modulation of activity following STN-HFS was significantly higher compared with that observed in intact (39.7%) and in SN-lesioned rats (35.4%). Furthermore, in EP-lesioned rats the most frequent response of PPN neurons following STN-HFS was a 5-20 s excitation, which was present in 76.6% of responsive neurons in comparison to 15.4% and 9.1% of neurons responsive in intact and in 6-hydroxydopamine-lesioned rats, respectively. Neurons responsive to STN-HFS in the three experimental groups showed either a sharp positively skewed distribution of interspike intervals or multisecond oscillations in autocorrelograms. The results support that STN-HFS modulates the PPN through a balance of excitatory and inhibitory influences, which may be independent from the dopaminergic nigral neurons. In the absence of inhibitory EP fibres, the direct excitatory influence exerted by the STN on the PPN appears to predominate.