Parkinson's Disease Symptoms Associated with Developing On-State Axial Symptoms Early after Subthalamic Deep Brain Stimulation.

Background: The relationship between axial symptoms in Parkinson's disease (PD) and subthalamic deep brain stimulation (STN-DBS) is still unclear. Purpose: We searched for particular clinical characteristics before STN-DBS linked to on-state axial problems after surgery. Methods: We retrospectively analyzed baseline motor, emotional and cognitive features from PD patients with early axial symptoms (within 4 years after STN-DBS) and late axial symptoms (after 4 years). We also considered a group of PD patients without axial symptoms for at least 4 years after surgery. Results: At baseline, early-axial PD patients (n = 28) had a higher on-state Unified Parkinson's Disease Rating Scale III (15.0 ± 5.6 to 11.6 ± 6.2, p = 0.020), higher axial score (2.4 ± 1.8 to 0.7 ± 1.0, p < 0.001) and worse dopaminergic response (0.62 ± 0.12 to 0.70 ± 0.11, p = 0.005), than non-axial PD patients (n = 51). Early-axial PD patients had short-term recall impairment, not seen in non-axial PD (36.3 ± 7.6 to 40.3 ± 9.3, p = 0.041). These variables were similar between late-axial PD (n = 18) and non-axial PD, but late-axial PD showed worse frontal dysfunction. Conclusions: PD patients with early axial symptoms after DBS may have a significantly worse presurgical motor phenotype, poorer dopaminergic response and memory impairment. This may correspond to a more severe form of PD.

Concurrent Akt, ERK1/2 and AMPK Activation by Obestatin Inhibits Apoptotic Signaling Cascades on Nutrient-Deprived PC12 Cells.

Targeting apoptosis in the ischemic penumbra is a rational therapeutic approach for restricting cerebral infarct volume after clinical stroke. The present work explored the capability of the obestatin peptide, as a novel approach to inhibit apoptotic signaling cascades on PC12 cells. According to the results, obestatin treatment significantly reduced nutrient deprivation-induced apoptotic cell death. The protective effects were related to the regulation of the anti-apoptotic protein, BCL-2, and the apoptotic protein caspase-3. This encompasses the control of apoptosis by the interplay between Akt, ERK1/2 and AMPK signaling pathways. The activation of Akt and AMPK was concomitant with the phosphorylation of their downstream targets, GSK3 and ACC, respectively. Besides, obestatin also causes FoxO1 nuclear export supporting the prevention of the apoptosome formation. The concurrent activation of Akt and AMPK by obestatin via the GPR39 receptor, supports a role for this system in the balance concerning the catabolic and the anabolic signaling to sustain cellular function and viability. Furthermore, these results provide both an insight into how the obestatin/GPR39 system regulates anti-apoptotic pathways, and a framework for ascertaining how this system can be optimally targeted in treatment of brain cell death after stroke.

Continuous Subcutaneous Apomorphine Infusion before Subthalamic Deep Brain Stimulation: A Prospective, Comparative Study in 20 Patients.

BACKGROUND: Studies comparing the clinical efficacy of apomorphine infusion (APO) with subsequent subthalamic deep brain stimulation (STN-DBS) in advanced Parkinson's disease (aPD) are currently lacking. Retrospective data have shown that patients treated with APO are usually older, have a more prolonged disease, and a more severe phenotype. OBJECTIVE: To compare the benefit of APO with that of STN-DBS on motor, non-motor, cognitive, and quality of life in the same patient when given sequentially. METHODS: We prospectively analyzed 20 aPD patients over 3 different treatment phases: baseline (optimized medical treatment), during APO treatment, and during subsequent STN-DBS treatment. The APO and STN-DBS phases were stable for 6 months, and evaluation of the different treatments was separated by 6 months. RESULTS: Compared to baseline, APO, and STN-DBS reduced mean daily off time by 70.5% and 89.3% (P = 0.012), respectively, and scores for Unified Parkinson's Disease Rating Scale (UPDRS) IV by 27.5% and 80.5% (P ≤ 0.001), Non-motor symptoms scale (NMSS) by 24.6% and 49.3% (P ≤ 0.001), Montgomery Asberg depression scale (MADRS) by 7.4% and 39.0% (P = 0.27), Starkstein apathy scale (SAS) by 51.1% and 39.9% (P = 0.734), Parkinson's disease sleep scale 2 (PDSS-2) by 25.7% and 56.7% (P ≤ 0.001), and Parkinson's disease questionnaire 39 item (PDQ-39) by 39.6% and 64.9% (P ≤ 0.001). Global cognition did not change with either therapy, but phonetic fluency worsened after STN-DBS compared to APO (P = 0.022). CONCLUSIONS: Both APO and STN-DBS improved motor and non-motor symptoms and quality of life compared to optimized medical treatment in aPD. Overall, STN-DBS was the most effective treatment, but APO showed a pronounced benefit on motor symptoms. Effective treatment for aPD should not be delayed, even when waiting for surgery.

Obestatin signalling counteracts glucocorticoid-induced skeletal muscle atrophy via NEDD4/KLF15 axis.

BACKGROUND: A therapeutic approach for the treatment of glucocorticoid-induced skeletal muscle atrophy should be based on the knowledge of the molecular mechanisms determining the unbalance between anabolic and catabolic processes and how to re-establish this balance. Here, we investigated whether the obestatin/GPR39 system, an autocrine signalling system acting on myogenesis and with anabolic effects on the skeletal muscle, could protect against chronic glucocorticoid-induced muscle atrophy. METHODS: In this study, we used an in vivo model of muscle atrophy induced by the synthetic glucocorticoid dexamethasone to examine the liaison molecules that define the interaction between the glucocorticoid receptor and the obestatin/GPR39 systems. The findings were extended to in vitro effects on human atrophy using human KM155C25 myotubes. RESULTS: KLF15 and FoxO transcription factors were identified as direct targets of obestatin signalling in the control of proteostasis in skeletal muscle. The KLF15-triggered gene expression program, including atrogenes and FoxOs, was regulated via KLF15 ubiquitination by the E3 ubiquitin ligase NEDD4. Additionally, a specific pattern of FoxO post-translational modification, including FoxO4 phosphorylation by Akt pathway, was critical in the regulation of the ubiquitin-proteasome system. The functional cooperativity between Akt and NEDD4 in the regulation of FoxO and KLF15 provides integrated cues to counteract muscle proteostasis and re-establish protein synthesis. CONCLUSIONS: The effective control of FoxO activity in response to glucocorticoid is critical to counteract muscle-related pathologies. These results highlight the potential of the obestatin/GPR39 system to fine-tune the effects of glucocorticoids on skeletal muscle wasting.

Continuous subcutaneous apomorphine in advanced Parkinson's disease patients treated with deep brain stimulation.

INTRODUCTION: Deep brain stimulation (DBS) is an effective therapy for patients with advanced Parkinson's disease (PD). However, sometimes, it is not sufficient to adequately control motor symptoms. We describe our experience with continuous subcutaneous apomorphine infusion (APO) in patients with DBS. METHODS: We undertook a retrospective analysis of all patients treated with DBS and APO at our centre over 12 years. Subjects were allocated to four groups: (1) APO temporarily before DBS, (2) APO after DBS complications before a new DBS, (3) APO after definitive DBS removal, and (4) APO in patients with DBS and declining response. Motor state and other parameters were analysed and compared for the different treatments. RESULTS: Data for 71 patients were evaluated. Group 1: (n = 18) patients improved their motor function significantly with both APO and DBS (off-hours before APO 5.4 ± 1.4; after APO 1.4 ± 1.2, p > 0.001; after DBS 0.7 ± 0.8, p < 0.001). Group 2: (n = 11) patients were found to have mild but significant worsening of motor state between the first DBS treatment (off-hours 0.7 ± 1.0) and APO (2.2 ± 1.5, p = 0.02), and improvement between APO and the second DBS treatment (off-hours 0.6 ± 0.8, p = 0.03). Group 3: (n = 12) patients had mild but significant worsening of motor function between DBS (off-hours 1.1 ± 1.0) and APO (2.0 ± 0.9, p = 0.03). Group 4: (n = 13) significant improvement in motor function was observed between DBS alone (off-hours 3.9 ± 2.6) and DBS combined with APO (2.2 ± 1.3, p = 0.03). CONCLUSION: In advanced PD, DBS may be not sufficient or may fail to control motor symptoms adequately. In these cases, APO, whether alone or in combination with DBS, is a good choice to improve the disease control.

Publisher Correction: Obestatin controls skeletal muscle fiber-type determination.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Improvement of Duchenne muscular dystrophy phenotype following obestatin treatment.

BACKGROUND: This study was performed to test the therapeutic potential of obestatin, an autocrine anabolic factor regulating skeletal muscle repair, to ameliorate the Duchenne muscular dystrophy (DMD) phenotype. METHODS AND RESULTS: Using a multidisciplinary approach, we characterized the ageing-related preproghrelin/GPR39 expression patterns in tibialis anterior (TA) muscles of 4-, 8-, and 18-week-old mdx mice (n = 3/group) and established the effects of obestatin administration at this level in 8-week-old mdx mice (n = 5/group). The findings were extended to in vitro effects on human immortalized DMD myotubes. An analysis of TAs revealed an age-related loss of preproghrelin expression, as precursor of obestatin, in mdx mice. Administration of obestatin resulted in a significant increase in tetanic specific force (33.0% ± 1.5%, P < 0.05), compared with control mdx mice. Obestatin-treated TAs were characterized by reduction of fibres with centrally located nuclei (10.0% ± 1.2%, P < 0.05) together with an increase in the number of type I fibres (25.2% ± 1.7%, P < 0.05) associated to histone deacetylases/myocyte enhancer factor-2 and peroxisome proliferator-activated receptor-gamma coactivator 1α axis, and down-regulation of ubiquitin E3-ligases by inactivation of FoxO1/4, indexes of muscle atrophy. Obestatin reduced the level of contractile damage and tissue fibrosis. These observations correlated with decline in serum creatine kinase (58.8 ± 15.2, P < 0.05). Obestatin led to stabilization of the sarcolemma by up-regulation of utrophin, α-syntrophin, ß-dystroglycan, and α7ß1-integrin proteins. These pathways were also operative in human DMD myotubes. CONCLUSIONS: These results highlight the potential of obestatin as a peptide therapeutic for preserving muscle integrity in DMD, thus allowing a better efficiency of gene or cell therapy in a combined therapeutic approach.

Obestatin controls skeletal muscle fiber-type determination.

Obestatin/GPR39 signaling stimulates skeletal muscle growth and repair by inducing both G-protein-dependent and -independent mechanisms linking the activated GPR39 receptor with distinct sets of accessory and effector proteins. In this work, we describe a new level of activity where obestatin signaling plays a role in the formation, contractile properties and metabolic profile of skeletal muscle through determination of oxidative fiber type. Our data indicate that obestatin regulates Mef2 activity and PGC-1α expression. Both mechanisms result in a shift in muscle metabolism and function. The increase in Mef2 and PGC-1α signaling activates oxidative capacity, whereas Akt/mTOR signaling positively regulates myofiber growth. Taken together, these data indicate that the obestatin signaling acts on muscle fiber-type program in skeletal muscle.

Growth hormone treatment enhances the functional recovery of sciatic nerves after transection and repair.

INTRODUCTION: Although nerves can spontaneously regenerate in the peripheral nervous system without treatment, functional recovery is generally poor, and thus there is a need for strategies to improve nerve regeneration. METHODS: The left sciatic nerve of adult rats was transected and immediately repaired by epineurial sutures. Rats were then assigned to one of two experimental groups treated with either growth hormone (GH) or saline for 8 weeks. Sciatic nerve regeneration was estimated by histological evaluation, nerve conduction tests, and rotarod and treadmill performance. RESULTS: GH-treated rats showed increased cellularity at the lesion site together with more abundant immunoreactive axons and Schwann cells. Compound muscle action potential (CMAP) amplitude was also higher in these animals, and CMAP latency was significantly lower. Treadmill performance increased in rats receiving GH. CONCLUSION: GH enhanced the functional recovery of the damaged nerves, thus supporting the use of GH treatment, alone or combined with other therapeutic approaches, in promoting nerve repair.

Hemifield dependence of responses to colour in human fusiform gyrus.

To investigate the hemifield dependence of visually evoked responses to colour in the human fusiform gyrus we recorded evoked potentials from subdural electrodes in a patient suffering from occipital epilepsy. The responses in the fusiform gyrus show a strong hemifield dependence and discriminate the onset from the offset of the stimulus. Additionally, we found responses to squares made of random dots, whereas no responses were found to squares with a homogeneous bright surface. Our findings further support the idea that the fusiform gyrus is related to colour and pattern perception. However, the hemifield dependence we found may indicate that further processing is required in order to combine information from both visual hemifields.

Evidence of basal temporo-occipital cortex involvement in stereoscopic vision in humans: a study with subdural electrode recordings.

Stereoscopic vision is based on small differences in both retinal images known as retinal disparities. We investigated the cortical responses to retinal disparities in a patient suffering from occipital epilepsy by recording evoked potentials to random dot stereograms (RDS) from subdural electrodes placed in the parieto-occipito-temporal junction, medial surface of the occipital lobe (pericalcarine cortex) and basal surface of the occipital and temporal lobes (fusiform gyrus). Clear responses to disparity present in RDS were found in the fusiform cortex. We observed that the fusiform responses discriminate the onset from the offset of the stimulus, correlation from uncorrelation, and they show a longer latency than responses found in the pericalcarine cortex. Our findings indicate that the fusiform area is involved in the processing of the stereoscopic information and shows responses that suggest a high level of stereoscopic processing.