Selective increase of in vivo firing frequencies in DA SN neurons after proteasome inhibition in the ventral midbrain

The impairment of protein degradation via the ubiquitin‐proteasome system (UPS) is present in sporadic Parkinson's disease (PD), and might play a key role in selective degeneration of vulnerable dopamine (DA) neurons in the substantia nigra pars compacta (SN). Further evidence for a causal role of dysfunctional UPS in familial PD comes from mutations in parkin, which results in a loss of function of an E3‐ubiquitin‐ligase. In a mouse model, genetic inactivation of an essential component of the 26S proteasome lead to widespread neuronal degeneration including DA midbrain neurons and the formation of alpha‐synuclein‐positive inclusion bodies, another hallmark of PD. Studies using pharmacological UPS inhibition in vivo had more mixed results, varying from extensive degeneration to no loss of DA SN neurons. However, it is currently unknown whether UPS impairment will affect the neurophysiological functions of DA midbrain neurons. To answer this question, we infused a selective proteasome inhibitor into the ventral midbrain in vivo and recorded single DA midbrain neurons 2 weeks after the proteasome challenge. We found a selective increase in the mean in vivo firing frequencies of identified DA SN neurons in anesthetized mice, while those in the ventral tegmental area (VTA) were unaffected. Our results demonstrate that a single‐hit UPS inhibition is sufficient to induce a stable and selective hyperexcitability phenotype in surviving DA SN neurons in vivo. This might imply that UPS dysfunction sensitizes DA SN neurons by enhancing ‘stressful pacemaking’.     

Biologically active aspidofractinine, rhazinilam, akuammiline, and vincorine alkaloids from Kopsia

Eleven new indole alkaloids, in addition to the previously reported rhazinal (1), and 14 other known alkaloids, were obtained from the Malayan Kopsia singapurensis, viz., kopsiloscines A-F (2-7), 16-epikopsinine (8), kopsilongine- N-oxide (9), 16-epiakuammiline (10), aspidophylline A (11), and vincophylline (12). The structures of these alkaloids were determined using NMR and MS analyses. Rhazinal (1), rhazinilam (17), and rhazinicine (18) showed appreciable cytotoxicity toward drug-sensitive as well as vincristine-resistant KB cells, while kopsiloscines A (2), B (3), and D (5) and aspidophylline A (11) were found to reverse drug-resistance in drug-resistant KB cells.     

Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones

PPAR gamma is required for fat cell development and is the molecular target of antidiabetic thiazolidinediones (TZDs), which exert insulin-sensitizing effects in adipose tissue, skeletal muscle, and liver. Unexpectedly, we found that inactivation of PPAR gamma in macrophages results in the development of significant glucose intolerance plus skeletal muscle and hepatic insulin resistance in lean mice fed a normal diet. This phenotype was associated with increased expression of inflammatory markers and impaired insulin signaling in adipose tissue, muscle, and liver. PPAR gamma-deficient macrophages secreted elevated levels of factors that impair insulin responsiveness in muscle cells in a manner that was enhanced by exposure to FFAs. Consistent with this, the relative degree of insulin resistance became more severe in mice lacking macrophage PPAR gamma following high-fat feeding, and these mice were only partially responsive to TZD treatment. These findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs.     

Multiple subpial lipomas with dumb-bell extradural extension through the intervertebral foramen without spinal dysraphism

BACKGROUND: Intradural subpial lipomas not associated with spinal dysraphism, account for less than 1% of spinal cord tumors. The simultaneous existence of multiple intradural subpial lipomas with dumb-bell extradural extension through the intervertebral foramen in the same patient without any evidence of spinal dysraphism has not been previously reported. CASE DESCRIPTION: A 38-year-old man presented with progressive spastic paraparesis, and weakness of right elbow extension and opposition of the medial three fingers. He also had ascending paraesthesia from the C6 dermatome to the saddle region and loss of joint and position sense of both lower limbs with hesitancy and precipitancy of micturition. There was no spinal tenderness, deformity, neurocutaneous markers, or spinal dysraphism. The total duration of illness was 11 years.The oblique views of the plain radiographs of the cervical spine revealed an enlarged right C7-D1 intervertebral foramen. The T1- and T2-weighted magnetic resonance (MR) images showed two intradural, hyperintense lesions (with extensive loss of signal on fat suppression sequences), one extending from C5 to D2 and the other opposite the C3-4 disc space. The parasagittal and axial images showed the extradural component of the lesion emerging from the right C7-D1 intervertebral foramen.At surgery, a C2 to D2 laminectomy was performed. The lipoma, enclosed in a fine pial membrane, was situated on the right posterolateral aspect of the cord. The right-sided nerve roots from the C6 to D1 levels were completely enmeshed by the lipoma. There was a separate superficial subpial lipoma adherent to the posterior aspect of the cord at the C3-4 level. A distinct area of normal cord was present between the two lesions. A subtotal decompression of the lesions including the component emerging through the right C7-D1 intervertebral foramen and a duraplasty were performed.At follow-up after 18 months, the posterior column impairment, lower limb hypoaesthesia, and right upper limb paraesthesia had improved. However, residual elbow extension and lower limb weakness, mild lower limb spasticity and sphincteric dysfunction persisted. CONCLUSIONS: The multiplicity of intradural subpial lipomas without spinal dysraphism points to a dysembryogenetic basis similar to that seen in patients with spinal dysraphism that results in lipomas, but in which the defect is not severe enough to give rise to coexisting vertebral and soft tissue anomalies. The dumb-bell extradural extension through the intervertebral foramen is extremely rare. The magnetic resonance imaging and surgical principles are discussed.