The current study examines the association between glucose induction of reactive oxygen species (ROS), mitochondrial (Mt) depolarization, and programmed cell death in primary neurons. In primary dorsal root ganglion (DRG) neurons, 45 mM glucose rapidly induces a peak rise in ROS corresponding to a 50% increase in mean Mt size at 6 h (P<0.001). This is coupled with loss of regulation of the Mt membrane potential (Mt membrane hyperpolarization, followed by depolarization, MMD), partial depletion of ATP, and activation of caspase-3 and -9. Glucose-induced activation of ROS, MMD, and caspase-3 and -9 activation is inhibited by myxothiazole and thenoyltrifluoroacetone (P<0.001), which inhibit specific components of the Mt electron transfer chain. Similarly, MMD and caspase-3 activation are inhibited by 100 microM bongkrekic acid (an inhibitor of the adenosine nucleotide translocase ANT). These results indicate that mild increases in glucose induce ROS and Mt swelling that precedes neuronal apoptosis. Glucotoxicity is blocked by inhibiting ROS induction, MMD, or caspase cleavage by specific inhibitors of electron transfer, or by stabilizing the ANT.

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Glutamate carboxypeptidase II (GCP II) inhibition has previously been shown to be protective against long-term neuropathy in diabetic animals. In the current study, we have determined that the GCP II inhibitor 2-(phosphonomethyl) pentanedioic acid (2-PMPA) is protective against glucose-induced programmed cell death (PCD) and neurite degeneration in dorsal root ganglion (DRG) neurons in a cell culture model of diabetic neuropathy. In this model, inhibition of caspase activation is mediated through the group II metabotropic glutamate receptor, mGluR3. 2-PMPA neuroprotection is completely reversed by the mGluR3 antagonist (S)-a-ethylglutamic acid (EGLU). In contrast, group I and III mGluR inhibitors have no effect on 2-PMPA neuroprotection. Furthermore, we show that two mGluR3 agonists, the direct agonist (2R,4R)-4-aminopyrrolidine-2, 4-dicarboxylate (APDC) and N-acetyl-aspartyl-glutamate (NAAG) provide protection to neurons exposed to high glucose conditions, consistent with the concept that 2-PMPA neuroprotection is mediated by increased NAAG activity. Inhibition of GCP II or mGluR3 may represent a novel mechanism to treat neuronal degeneration under high-glucose conditions.

Insulin-like growth factor-I (IGF-I) in vivo or in the presence of other permissive factors can promote myelination in the central nervous system. In the current study, we examine the role of IGF-I in the myelination of peripheral nerves. In rat cocultures of dorsal root ganglia (DRG) and Schwann cells (SC) grown in serum- and insulin-free defined medium, IGF-I induces a dose dependent upregulation in myelin proteins such as P0, corresponding to maximal SC ensheathment. Furthermore, IGF-I is essential in promoting a dose-dependent, long-term myelination of DRG sensory axons. In the absence of IGF-I, axons and SC survive, but fail to myelinate. In the presence of 10 nM IGF-I, 59% of axons are myelinated at 21 days, whereas in the absence of IGF-I myelination fails to occur. Maximum SC ensheathment occurs 48 hours after addition of IGF-I. If IGF-I is withdrawn at 48 hours, axon segregation by SC persists, however, most axons and SC do not exhibit a one-to-one relationship and little myelination is observed. IGF-I is important in myelination and is critical not only for initial SC ensheathment of the axon and upregulation of myelin proteins, but also for sustained myelination. Furthermore, IGF-I associated axonal size is not the sole determinant for myelination.

Background:Mechanical thrombectomy devices are gaining popularity in large vessel occlusions where chemical thrombolysis is usually futile. MERCI, Multi-MERCI, Penumbra and SWIFT trails have elevated the status of mechanical thrombectomy from being a complementary treatment modality to mainstream stroke intervention. The aim of this study was to compare our immediate recanalization rates with available mechanical devices.Materials and Methods:A retrospective review from March 2009 to August 2012 was performed on patients who underwent mechanical thrombectomy for large vessel occlusion. Cases where IATPA and/or balloon angioplasty was performed without mechanical thrombectomy were excluded from the study. Recanalization rates were assessed immediately post-procedure by follow-up angiography. TICI scores were used to quantify the extent of recanalization and the residual clot burden.Results:Twenty two procedures were performed on 20 patients using Merci (MER):5; Penumbra (PEN):11; Solitaire-FR (SOL):6. Two patients underwent intervention using both Merci and Penumbra devices. The M:F ratio was 1.2:1. The most common vascular territory involved was the right MCA (9/20) followed by left MCA (5/20), left ICA (2/20), basilar (3/20) and vertebral arteries (1/20). The average door to needle time was 210 minutes [MER: 184.4; PEN: 249.2; SOL: 162]. Additional procedures were performed in 63.4% (14/22) of the patients [MER: 80% (4/5); PEN: 72.7% (8/11) and SOL: 33.3% (2/6)]. Vasospasm was observed in MER: 20% (1/5); PEN: 9.1% (1/11); SOL: 0% (0/6)]. Complete recanalization was achieved in 59.1% (13/22) [MER: 40% (2/5); PEN: 45.5% (5/11); SOL: 100% (6/6)]. The rate of complete recanalization was statistically significant for the Solitaire group vs. the MERCI group (P=0.0062) as well as the Penumbra group (0.0025). The average pre-procedure TICI was 0.4 [MER: 0.6; PEN: 0.3; SOL: 0.3], while the average post-procedure TICI was 2.5 [MER: 2.4; PEN: 2.3; SOL: 3.0].Conclusions:The study reveals a higher rate of angiographic recanalization using the Solitaire-FR device, requiring a lesser number of passes and other associated procedures as compared to MERCI and Penumbra. Thus, Stentrievers (Solitaire-FR) are advantageous in faster device delivery and quick flow restoration. However, future prospective randomized large trials are required to confirm these early results.