Reduced oxidative muscle metabolism in chronic fatigue syndrome

The purpose of this study was to determine if chronic fatigue syndrome (CSF) is characterized by abnormalities in oxidative muscle metabolism. Patients with CFS according to Centers for Disease Control (CDC) criteria (n = 22) were compared to normal sedentary subjects (n = 15). CFS patients were also tested before and 2 days after a maximal treadmill test. Muscle oxidative capacity was measured as the maximal rate of postexercise phosphocreatine (PCr) resynthesis using the ADP model (V_max) in the calf muscles using ³¹P magnetic resonance spectroscopy. V_max was significantly reduced in CFS patients (39.6 ± 2.8 mmol/L/min, mean ± SE) compared to controls (53.8 ± 2.8 mmol/L/min). Two days postexercise there was no change in resting inorganic phosphate (Pi)/PCr or V_max in the CFS patients (n = 14). In conclusion, oxidative metabolism is reduced in CFS patients compared to sedentary controls. In addition, a single bout of strenuous exercise did not cause a further reduction in oxidative metabolism, or alter resting Pi/PCr ratios. © 1996 John Wiley & Sons, Inc.     

Skeletal muscle oxidative capacity in amyotrophic lateral sclerosis

Introduction: Mitochondrial dysfunction in the motor neuron has been suspected in amyotrophic lateral sclerosis (ALS). If mitochondrial abnormalities are also found in skeletal muscle, assessing skeletal muscle could serve as an important biomarker of disease progression. Methods: Using ³¹P magnetic resonance (³¹P‐MRS) and near infrared (NIRS) spectroscopy, we compared the absolute values and reproducibility of skeletal muscle oxidative capacity in people with ALS (n = 6) and healthy adults (young, n = 7 and age‐matched, n = 4). Results: ALS patients had slower time constants for phosphocreatine (PCr) and muscle oxygen consumption (mVO₂) compared with young, but not age‐matched controls. The coefficient of variation for the time constant was 10% (SD = 2.8%) and 17% (SD = 6.2%) for PCr and mVO₂, respectively. Conclusions: People with ALS had, on average, a small but not statistically significant, impairment in skeletal muscle mitochondrial function measured by both ³¹P‐MRS and NIRS. Both methods demonstrated good reproducibility. Muscle Nerve 50 : 767–774, 2014     

Vastus lateralis NA+‐K+‐ATpase activity,protein, and isoform distribution in chronic obstructive pulmonary disease

In this study we investigate the hypothesis that protein abundance, isoform distribution, and maximal catalytic activity of sodium–potassium–adenosine triphosphatase (Na⁺‐K⁺‐ATPase) would be altered in muscle of patients with moderate to severe chronic obstructive pulmonary disease (COPD). Tissue samples were obtained from the vastus lateralis of 10 patients with COPD (mean ± SE: age = 67 ± 2.9 years; FEV₁ = 39 ± 5.5%) and 10 healthy, matched controls (CON: age = 68 ± 2 years; FEV₁ = 114 ± 4.2%). The samples were assessed for maximal catalytic activity (V_max) of the enzyme using the K⁺‐stimulated 3‐O‐methylfluorescein‐phosphatase (3‐O‐MFPase) assay, enzyme abundance using the [³H]‐ouabain assay, and isoform content of both α (α₁, α₂, α₃) and β (β₁, β₂, β₃) using Western blot techniques. A 19.4% lower (P < 0.05) V_max was observed in COPD compared with CON (90.7 ± 6.7 vs. 73.1 ± 4.7 nmol · mg protein^?1 h^?1). No differences between groups were observed for pump concentration (259 ± 15 vs. 243 ± 17 pmol · g wet weight). For the isoforms, α₁ was decreased by 28% (P < 0.05), and α₂ was increased by 12% (P < 0.05) in COPD compared with CON. No differences between groups were observed for α₃ or for the β isoforms. We conclude that moderate COPD compromises V_max, which occurs in the absence of changes in pump abundance. The reduction in V_max could be due to a shift in isoform expression (α₁, α₂), alterations in intrinsic regulation, or to structural changes in the enzyme. The changes observed in the catalytic activity of the pump could have major effects on membrane excitability and fatigability, which are typically compromised in COPD. Muscle Nerve, 2009     

Tai Chi Improves Brain Metabolism and Muscle Energetics in Older Adults

BACKGROUND AND PURPOSE

Tai Chi is a mind‐body exercise that has been shown to improve both mental and physical health. As a result, recent literature suggests the use of Tai Chi to treat both physical and psychological disorders. However, the underlying physiological changes have not been characterized. The aim of this pilot study is to assess the changes in brain metabolites and muscle energetics after Tai Chi training in an aging population using a combined brain‐muscle magnetic resonance spectroscopy (MRS) examination.

METHODS

Six healthy older adults were prospectively recruited and enrolled into a 12‐week Tai Chi program. A brain ¹H MRS and a muscle ³¹P MRS were scanned before and after the training, and postprocessed to measure N‐acetylaspartate to creatine (NAA/Cr) ratios and phosphocreatine (PCr) recovery time. Wilcoxon‐signed rank tests were utilized to assess the differences between pre‐ and post‐Tai Chi training.

RESULTS

A significant within‐subject increase in both the NAA/Cr ratios (P = .046) and the PCr recovery time (P = .046) was observed between the baseline and the posttraining scans. The median percentage changes were 5.38% and 16.51% for NAA/Cr and PCr recovery time, respectively.

CONCLUSIONS

Our pilot study demonstrates significant increase of NAA/Cr ratios in posterior cingulate gyrus and significantly improved PCr recovery time in leg muscles in older adults following short‐term Tai Chi training, and thus provides insight into the beneficial mechanisms.     

Homeostatic adaptations in brain energy metabolism in mouse models of Huntington disease

Impairment of energy metabolism is a key feature of Huntington disease (HD). Recently, we reported longitudinal neurochemical changes in R6/2 mice measured by in-vivo proton magnetic resonance spectroscopy (¹H MRS; Zacharoff et al, 2012). Here, we present similar ¹H MRS measurements at an early stage in the milder Q111 mouse model. In addition, we measured the concentration of ATP and inorganic phosphate (P_i), key energy metabolites not accessible with ¹H MRS, using ³¹P MRS both in Q111 and in R6/2 mice. Significant changes in striatal creatine and phosphocreatine were observed in Q111 mice at 6 weeks relative to control, and these changes were largely reversed at 13 weeks. No significant change was detected in ATP concentration, in either HD mouse, compared with control. Calculated values of [ADP], phosphorylation potential, relative rate of ATP synthase (v/V_max(ATP)), and relative rate of creatine kinase (v/V_max(CK)) were calculated from the measured data. ADP concentration and v/V_max(ATP) were increased in Q111 mice at 6 weeks, and returned close to normal at 13 weeks. In contrast, these parameters were normal in R6/2 mice. These results suggest that early changes in brain energy metabolism are followed by compensatory shifts to maintain energetic homeostasis from early ages through manifest disease.     

Frontal lobe bioenergetic metabolism in depressed adolescents with bipolar disorder: a phosphorus-31 magnetic resonance spectroscopy study

Shi X‐F, Kondo DG, Sung Y‐H, Hellem TL, Fiedler KK, Jeong E‐K, Huber RS, Renshaw PF. Frontal lobe bioenergetic metabolism in depressed adolescents with bipolar disorder: a phosphorus‐31 magnetic resonance spectroscopy study. Bipolar Disord 2012: 14: 607–617. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: To compare the concentrations of high‐energy phosphorus metabolites associated with mitochondrial function in the frontal lobe of depressed adolescents with bipolar disorder (BD) and healthy controls (HC). Methods: We used in vivo phosphorus‐31 magnetic resonance spectroscopy (³¹P‐MRS) at 3 Tesla to measure phosphocreatine (PCr), beta‐nucleoside triphosphate (β‐NTP), inorganic phosphate (Pi), and other neurometabolites in the frontal lobe of eight unmedicated and six medicated adolescents with bipolar depression and 24 adolescent HCs. Results: Analysis of covariance, including age as a covariate, revealed differences in PCr (p = 0.037), Pi (p = 0.017), and PCr/Pi (p = 0.002) between participant groups. Percentage neurochemical differences were calculated with respect to mean metabolite concentrations in the HC group. Post‐hoc Tukey–Kramer analysis showed that unmedicated BD participants had decreased Pi compared with both HC (17%; p = 0.038) and medicated BD (24%; p = 0.022). The unmedicated BD group had increased PCr compared with medicated BD (11%; p = 0.032). The PCr/Pi ratio was increased in unmedicated BD compared with HC (24%; p = 0.013) and with medicated BD (39%; p = 0.002). No differences in β‐NTP or pH were observed. Conclusions: Our results support the view that frontal lobe mitochondrial function is altered in adolescent BD and may have implications for the use of Pi as a biomarker. These findings join volumetric studies of the amygdala, and proton MRS studies of n‐acetyl aspartate in pointing to potential differences in neurobiology between pediatric and adult BD.     

Bioenergetics and intermuscular fat in chronic obstructive pulmonary disease‐associated quadriceps weakness

Introduction: Chronic obstructive pulmonary disease (COPD) is associated with metabolic abnormalities in muscles of the lower limbs, but it is not known whether these abnormalities are generalized or limited to specific muscle groups, nor is there an easy way of predicting their presence. Methods: Metabolism in the quadriceps and biceps of 14 COPD patients and controls was assessed during sustained contraction using 31‐phosphorus magnetic resonance spectroscopy (³¹P MRS). T1 MRI was used to measure quadriceps intermuscular adipose tissue (IMAT). Results: COPD patients had prolonged quadriceps phosphocreatine time (patients: 38.8 ± 12.7 s; controls: 25.2 ± 10.6 s; P = 0.006) and a lower pH (patents: 6.88 ± 0.1; controls: 6.99 ± 0.06; P = 0.002). Biceps measures were not significantly different. IMAT was associated with a nadir pH <7.0 (area under the curve = 0.84). Conclusions: Anaerobic metabolism during contraction was characteristic of quadriceps, but not biceps, muscles of patients with COPD and was associated with increased IMAT. Because IMAT can be assessed quickly by conventional MRI, it may be a useful approach for identifying patients with abnormal muscle bioenergetics. Muscle Nerve 51 : 214–221, 2015     

Positron emission tomography quantification of serotonin transporter binding in medication‐free bipolar disorder

Objectives: Bipolar disorder (BD) is associated with abnormalities in the serotonin transporter (5‐HTT), but specific in vivo findings have been discrepant. Using positron emission tomography (PET) and [¹¹C]DASB, we compared 5‐HTT binding between unmedicated depressed BD subjects and healthy volunteers (HVs). Experimental Design: 5‐HTT binding in six brain regions was compared between 17 depressed, unmedicated BD subjects and 31 HVs, using the outcome measure of V_T/f_P (proportional to the total number of available transporters). Alternative outcome measures were examined as well. 47% of BD were BP I; and 65% reported a prior suicide attempt. Principal Observations: 5‐HTT binding (V_T/f_P) did not differ between BD and HV groups considering six brain regions of interest simultaneously (P = 0.24). In contrast, alternative outcome measures (BP_F*, BP_P*, and BP_ND*) indicated lower binding in BD compared with HV across these six regions of interest (BP_F*: P = 0.047; BP_P*: P = 0.032; BP_ND*: P = 0.031). 5‐HTT binding was unrelated to suicide attempt history, depression severity, bipolar subtype, or history of past substance use disorder. Conclusions: Choice of outcome measure strongly affects comparisons of serotonin transporter binding using PET with [¹¹C]DASB. We do not find evidence of abnormal 5‐HTT binding in bipolar depression using our primary outcome measure, V_T/f_P. However, we did observe lower 5‐HTT binding in BD with alternative outcome measures that are frequently used with [¹¹C]DASB. Relative merits and assumptions of different outcome measures are discussed. Evaluation in larger samples and during different mood states, including remission, is warranted. Synapse 70:24–32, 2016. . © 2015 Wiley Periodicals, Inc.     

Long‐Term Study of Brain 1H‐MRS Study in Multiple Sclerosis: Effect of Glatiramer Acetate Therapy on Axonal Metabolic Function and Feasibility of Long‐Term 1H‐MRS Monitoring in Multiple Sclerosis

Glatiramer acetate (GA) has several putative mechanisms of action with the potential of limiting sublethal axonal injury in the central nervous system (CNS). Brain proton magnetic resonance spectroscopy (¹H‐MRS) allows in vivo examination of axonal integrity by quantifying the neuronal marker N‐acetylaspartate (NAA), often expressed as a ratio to creatine (Cr). We showed that treatment with GA led to improvement in NAA/Cr over a 2‐year period. We now report the results of this ongoing study after 4 years of annual brain ¹H‐MRS examinations. Compared to baseline, at year 4, patients receiving continuous GA therapy showed a 12.7% increase in NAA/Cr and (P= .03) in the multivoxel brain volume of interest (VOI) studied and by 9.6% (P= .04) in the normal‐appearing white matter within the VOI. Three patients in the control group who began therapy with GA during the course of the study showed similar increases in NAA/Cr after the first year of therapy. These data support the long‐term effect of GA on maintaining axonal metabolic function and protection from sublethal injury as well as the feasibility of employing brain ¹H‐MRS in long‐term investigative studies in MS.     

Phosphorus magnetic resonance spectroscopy in malformations of cortical development

Purpose: The aim of this study was to evaluate phospholipid metabolism in patients with malformations of cortical development (MCDs). Methods: Thirty‐seven patients with MCDs and 31 control subjects were studied using three‐dimensional phosphorus magnetic resonance spectroscopy (³¹P‐MRS) at 3.0 T. The voxels in the lesions and in the frontoparietal cortex of the control subjects were compared (the effective volumes were 12.5 cm³). Robust quantification methods were applied to fit the time‐domain data to the following resonances: phosphoethanolamine (PE); phosphocholine (PC); inorganic phosphate (Pi); glycerophosphoethanolamine (GPE); glycerophosphocholine (GPC); phosphocreatine (PCr); and α‐, β‐, and γ‐adenosine triphosphate (ATP). We also estimated the total ATP (ATP_t = α‐+β‐+γ‐ATP), phosphodiesters (PDE = GPC+GPE), phosphomonoesters (PME = PE+PC), and the PME/PDE, PCr/ATP_t and PCr/Pi ratios. The magnesium (Mg²⁺) levels and pH values were calculated based on PCr, Pi, and β‐ATP chemical shifts. Key Findings: Compared to controls and assuming that a p‐value < 0.05 indicates statistical significance, the patients with MCDs exhibited significantly lower pH values and higher Mg²⁺ levels. In addition, the patients with MCDs had lower GPC and PDE and an increased PME/PDE ratio. Significance: Mg²⁺ and pH are important in the regulation of bioenergetics and are involved in many electrical activity pathways in the brain. Our data support the idea that neurometabolic impairments occur during seizure onset and propagation. The GPC, PDE, and PME/PDE abnormalities also demonstrate that there are membrane turnover disturbances in patients with MCDs.     

Aerobic training in patients with anoctamin 5 myopathy and hyperckemia

Introduction: Anoctamin 5 deficiency has recently been defined to cause limb‐girdle muscular dystrophy type 2L (LGMD2L) with pronounced hyperCKemia. No treatment interventions have been made so far in this condition. Methods: In 6 patients with LGMD2L, we studied the effect of home‐based, pulse‐watch monitored, moderate‐intensity exercise on a cycle ergometer for 30 minutes, 3 times weekly, for 10 weeks. Plasma creatine kinase (CK) was assessed before, during, and after the program as a marker of muscle damage. Primary outcome measures were maximum oxygen uptake (VO_2max) and time in the 5‐repetitions‐sit‐to‐stand test (FRSTST). Results: Training resulted in improvements in VO_2max (27 ± 7%; P = 0.0001) and FRSTST time (35 ± 12%; P = 0.007). Improvements in physiologic and functional muscle testing were accompanied by stable CK levels and no reports of adverse effects. Conclusions: These findings suggest that supervised aerobic exercise training is safe and effective in improving oxidative capacity and muscle function in patients with anoctamin 5 deficiency. Muscle Nerve 50 : 119–123, 2014     

Satellite cell pool expansion is affected by skeletal muscle characteristics

Introduction: We investigated changes in satellite cell (SC) pool size after an acute bout of strenuous exercise and evaluated the influence of baseline SC count and fiber type. Methods: Participants completed a downhill running (DHR) intervention (5 × 8 min, 2‐min rest; 80% VO _2max; ?10% gradient). Muscle biopsies were taken 7 days before VO _2max and 7–9 days after the DHR intervention. Delayed‐onset muscle soreness (DOMS) and creatine kinase activity (CK) were measured on days 1, 2, 7, and 9 post‐DHR. SCs were identified by Pax7 and laminin staining. Relative distribution of MHC isoforms was determined by electrophoresis. Results: DOMS and CK peaked on day 1 post‐DHR (P < 0.01). The SC pool increased (26%) after DHR (P = 0.005). SCs/total myonuclei after recovery correlated with baseline SCs (r = 0.979, P = 0.003) and VO _2max (r = 0.956, P = 0.011), whereas change in SC pool (Pax7⁺ cells/total myonuclei: recovery minus baseline) tended to correlate with percent MHC II (r = 0.848; P = 0.06). Conclusion: Interindividual physiological characteristics affect SC pool expansion after a single bout of DHR and are influenced by VO _2max. Muscle Nerve, 2013     

Postexercise phosphocreatine resynthesis is slowed in multiple sclerosis

To determine whether skeletal muscle oxidative metabolism is impaired in multiple sclerosis (MS), ³¹ phosphorus magnetic resonance spectroscopy was used to measure the rate of intramuscular phosphocreatine (PCr) resynthesis following exercise in MS and controls. Thirteen MS patients underwent intermittent isometric tetanic contractions of the dorsiflexor muscles elicited by stimulation of the peroneal nerve. Eight healthy control subjects performed voluntary isometric exercise of the same muscles. During exercise, there were no differences between groups in the fall of either PCr or pH. However, the half-time (T-_1/2) of PCr recovery following exercise was significantly longer in MS (2.3 ± 0.3 min) compared to controls (1.2 ± 0.1 min, P < 0.02). These data provide evidence of slowed PCr resynthesis following exercise in MS, which indicates impaired oxidative capacity in the skeletal muscle of this group. This finding suggests that intramuscular changes consistent with deconditioning may be important in the altered muscle function of persons with MS. © 1994 John Wiley & Sons, Inc.     

Lipoic (thioctic) acid increases brain energy availability and skeletal muscle performance as shown by in vivo31P-MRS in a patient with mitochondrial cytopathy

A woman affected by chronic progressive external ophthalmoplegia and muscle mitochondrial DNA deletion was studied by phosphorus magnetic resonance spectroscopy (³¹P-MRS) prior to and after 1 and 7 months of treatment with oral lipoic acid. Before treatment a decreased phosphocreatine (PCr) content was found in the occipital lobes, accompanied by normal inorganic phosphate (Pi) level and cytosolic pH. Based on these findings, we found a high cytosolic adenosine diphosphate concentration [ADP] and high relative rate of energy metabolism together with a low phosphorylation potential. Muscle MRS showed an abnormal work-energy cost transfer function and a low rate of PCr recovery during the post-exercise period. All of these findings indicated a deficit of mitochondrial function in both brain and muscle. Treatment with 600 mg lipoic acid daily for 1 month resulted in a 55% increase of brain [PCr], 72% increase of phosphorylation potential, and a decrease of calculated [ADP] and rate of energy metabolism. After 7 months of treatment MRS data and mitochondrial function had improved further. Treatment with lipoate also led to a 64% increase in the initial slope of the work-energy cost transfer function in the working calf muscle and worsened the rate of PCr resynthesis during recovery. The patient reported subjective improvement of general conditions and muscle performance after therapy. Our results indicate that treatment with lipoate caused a relevant increase in levels of energy available in brain and skeletal muscle during exercise.     

Brain GABA levels across psychiatric disorders: A systematic literature review and meta‐analysis of 1H‐MRS studies

The inhibitory gamma‐aminobutyric acid (GABA) system is involved in the etiology of most psychiatric disorders, including schizophrenia, autism spectrum disorder (ASD) and major depressive disorder (MDD). It is therefore not surprising that proton magnetic resonance spectroscopy (¹H‐MRS) is increasingly used to investigate in vivo brain GABA levels. However, integration of the evidence for altered in vivo GABA levels across psychiatric disorders is lacking. We therefore systematically searched the clinical ¹H‐MRS literature and performed a meta‐analysis. A total of 40 studies (N = 1,591) in seven different psychiatric disorders were included in the meta‐analysis: MDD (N = 437), schizophrenia (N = 517), ASD (N = 150), bipolar disorder (N = 129), panic disorder (N = 81), posttraumatic stress disorder (PTSD) (N = 104), and attention deficit/hyperactivity disorder (ADHD) (N = 173). Brain GABA levels were lower in ASD (standardized mean difference [SMD] = ?0.74, P = 0.001) and in depressed MDD patients (SMD = ?0.52, P = 0.005), but not in remitted MDD patients (SMD = ?0.24, P = 0.310) compared with controls. In schizophrenia this finding did not reach statistical significance (SMD = ?0.23, P = 0.089). No significant differences in GABA levels were found in bipolar disorder, panic disorder, PTSD, and ADHD compared with controls. In conclusion, this meta‐analysis provided evidence for lower brain GABA levels in ASD and in depressed (but not remitted) MDD patients compared with healthy controls. Findings in schizophrenia were more equivocal. Even though future ¹H‐MRS studies could greatly benefit from a longitudinal design and consensus on the preferred analytical approach, it is apparent that ¹H‐MRS studies have great potential in advancing our understanding of the role of the GABA system in the pathogenesis of psychiatric disorders. Hum Brain Mapp 37:3337–3352, 2016. © 2016 Wiley Periodicals, Inc.     

Slower recovery of muscle phosphocreatine in malignant hyperthermia-susceptible individuals assessed by 31P-MR spectroscopy

Our aim was to develop an exercise protocol using ³¹P-magnetic resonance spectroscopy (³¹P-MRS), which can discriminate between malignant hyperthermia-susceptible (MHS) individuals and controls. MRS spectra of the forearm muscles were recorded at rest, during and after a standardized exercise protocol in 10 MHS patients and compared with spectra obtained in 10 controls. There was no difference in resting intracellular pH (pHi) or PCr/ (Pi+PCr) ratio between the groups (PCr = phosphocreatine, Pi = inorganic phosphorus). At the end of the exercise and during the initial recovery phase, the pHi and PCr/(Pi+PCr) ratio were significantly lower in the MHS group ([pHi: 6.37 (0.07) for MHS vs 6.70 (0.05) for controls, P < 0.005; PCr/(Pi+PCr): 0.784 (0.017) for MHS vs 0.954 (0.020) for controls, P < 0.0005]). For PCr/ (Pi+PCr), complete separation between the two groups was observed during the initial recovery phase. The mean recovery time of PCr/ (Pi+PCr) was 0.57 min for the control group and 1.28 min for the MHS group. The slower recovery of PCr/ (Pi+PCr) is likely to be caused by a combination of several factors, including the lower pHi in MHS subjects at the start of recovery (inhibiting ATP production) and excessive sarcoplasmic calcium overload (causing continued enzyme activation and ATP consumption). Our exercise protocol can be a valuable adjunct to discriminate between MHS and non susceptible subjects. Received: 10 July 1996 Received in revised form: 7 August 1997 Accepted: 11 August 1997     

Cerebral ischemia and white matter edema in experimental hydrocephalus: a combined in vivo MRI and MRS study

T₂ and diffusion weighted MRI, as well as ³¹P and ¹H MRS were performed in kaolin-induced hydrocephalic rats. Extracellular white matter edema was detected in the early stages of progressive hydrocephalus. Phosphocreatine (PCr)/inorganic phosphate (Pi) ratios in hydrocephalic animals were decreased compared to controls, and lactate was detected during the acute and chronic stages of hydrocephalus. These MR spectroscopic results are indicative of a compromised energy metabolism and suggest the occurrence of cerebral ischemia in experimental hydrocephalus.     

Brain translocator protein occupancy by ONO‐2952 in healthy adults: A Phase 1 PET study using [11C]PBR28

ONO‐2952, a novel antagonist of translocator protein 18 kDa (TSPO), binds with high affinity to TSPO in rat brain and human tumor cell line membrane preparations. This study used the TSPO‐specific PET radioligand [¹¹ C]PBR28 to confirm binding of ONO‐2952 to brain TSPO in human subjects, and evaluate brain TSPO occupancy and its relationship with ONO‐2952 plasma concentration. Sixteen healthy subjects received a single oral dose of 200, 60, 20, or 6 mg ONO‐2952 (n = 4 per dose). Two PET scans with [¹¹ C]PBR28 were conducted ≤7 days apart: at baseline and 24 h after ONO‐2952 administration. [¹¹ C]PBR28 regional distribution volume (V_T) was derived with kinetic modeling using the arterial input function and a two tissue compartment model. Nonspecific binding (V_ND) was obtained on an individual basis for each subject using linear regression as the x‐intercept of the Lassen plot. The binding potential relative to V_ND (BP_ND) was derived as the difference between V_T in the ROI (V_T ROI) and V_ND, normalized to V_ND; BP_ND = (V_T ROI – V_ND)/V_ND. TSPO occupancy was calculated as the change in BP_ND (ΔBP_ND) from individual's baseline scan to the on‐medication scan to the baseline BP_ND value. TSPO occupancy by ONO‐2952 was dose dependent between 20–200 mg, approaching saturation at 200 mg both in the whole brain and in 15 anatomic regions of interest (ROI). Estimated K_i values ranged from 24.1 to 72.2 nM. This open‐label, single‐center, single‐dose study demonstrated engagement of ONO‐2952 to brain TSPO. The relationship between pharmacokinetics and TSPO occupancy observed in this study support the hypothesis that ONO‐2952 could potentially modulate neurosteroid production by binding to brain TSPO.     

Alterations in 5‐HT2A receptor binding in various brain regions among 6‐hydroxydopamine‐induced Parkinsonian rats

The serotonergic system has close interactions with the dopaminergic system and is strongly implicated in the pathophysiological mechanisms and therapeutic paradigms of Parkinson's disease (PD). This study aims to investigate regional changes in 5‐hydroxytryptamine (5‐HT) 2A receptors in the rat brain 3 weeks after unilateral medial forebrain bundle lesion by 6‐hydroxydopamine (6‐OHDA). 5‐HT 2A receptor distributions and alterations in the postmortem rat brain were detected by [³H]ketanserin‐binding autoradiography. In the 6‐OHDA‐induced Parkinson's rat model, nigrostriatal dopaminergic neuron loss significantly mediated the decreased [³H]ketanserin binding, predominantly in the agranular insular cortex (17.3%, P = 0.03), cingulate cortex (18.2%, P < 0.001), prefrontal cortex (8%, P = 0.043), primary somatosensory cortex (17.7%, P = 0.002), and caudate putamen (14.5%, P = 0.02) compared to controls while a profound reduction of tyrosine hydroxylase (TH) immunostaining in the striatum was also observed. Alterations in [³H]ketanserin binding in the examined brain areas may represent the specific regions that mediate cognitive dysfunctions via the serotonin system. The downregulation of 5‐HT_2A receptor binding in this study also provides indirect evidence for plasticity in the serotonergic system in the rat brains. This study contributes to a better understanding of the critical roles of 5‐HT_2A receptors in treating neurodegenerative disorders and implicates 5‐HT_2A receptors as a novel therapeutic target in the treatment of PD. Synapse 64:224–230, 2010. © 2009 Wiley‐Liss, Inc.     

Direct electrical stimulation of rat soleus during denervation-reinnervation

The effect of direct, low-frequency electrical stimulation (at 10 Hz continuously 8 h daily) of muscle on isometric twitch contractile properties of adult rat soleus was observed during denervation and reinnervation. The normal and the bilaterally sciatic nerve crush-denervated groups were implanted with unilateral juxtamuscular electrodes to stimulate the soleus muscle in one limb. After 10, 15, 20, 25, and 30 days of electrical stimulation (2- to 4-mA pulses at 4 ms duration) the normal control, normal-stimulated, crush-denervated control, and crush-denervated-stimulated soleus muscles (N = 6) were evaluated in vitro by massively field stimulating the muscles in physiologic buffer (pH 7.2) at 23 to 24°C. The parameters of isometric twitch contraction measured were latent period (LP), maximum isometric twitch tension (P_t), contraction time (CT), maximum rate of isometric twitch tension (V_t^max), and half-relaxation time (HRT). In normal muscle, 25 and 30 days of electrical stimulation produced significant (P < 0.05) changes: muscle hypertrophy (26.5 and 16.6%, respectively), decline in the P_t (23.4 and 12.1%, respectively), and decrease in the (V_t^max) (17.3 and 21.6%, respectively). For the same periods, compared with the crush-denervated control, the crush-denervated-stimulated muscles also showed significant (P < 0.05) changes: prolongation of the LP. (22.9 and 26.5%), decline in the P_t (24.5 and 31.6%), and decrease in the V_t^max (27.7 and 33.3%). These results, therefore, suggest that the long-term (200 to 240 h) direct, lowfrequency (10 Hz) electrical stimulation may impair the mechanism of isometric twitch development in slow-twitch muscle of the rat. However, our study does not prove that this pattern of electrostimulation can significantly alter the course of self-reinnervation in muscle.