Experimental neurology
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Experimental neurology · Apr 2012
ReviewEmerging role of microglial kinin B1 receptor in diabetic pain neuropathy.
Nowadays diabetes mellitus has reached epidemic level and is considered as the primary cause of foot amputation and pain neuropathy. The classical theories explaining the development of diabetic pain neuropathy include the imbalance of neuronal biochemical pathways (Polyol pathway, Na(+)/K(+) ATPase pump, AGE, ROS) and microangiopathy which promote nerve fibers depolarization, sensitization, ectopic discharges, demyelization and ultimately neuronal death. However, the current pharmacotherapy targeting those pathways brings variable, not always satisfactory and temporal relief in patients experiencing diabetic pain neuropathy. ⋯ A few selective B1R antagonists have been fully characterized in animal models although small molecules orally active are urgently needed for targeting human B1R on CNS microglia. Thus far, the pharmacological blockade of kinin B1R in various animal paradigms or its genetic deletion in B1R knock-out mice failed to cause unwanted side effects, making this approach feasible. This is consistent with the highly inducible feature of this atypical G-protein coupled receptor whose expression can be seen as the alarming signature of immune and inflammatory diseases, notably diabetes mellitus.
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Experimental neurology · Apr 2012
ReviewPropentofylline, a CNS glial modulator does not decrease pain in post-herpetic neuralgia patients: in vitro evidence for differential responses in human and rodent microglia and macrophages.
There is a growing body of preclinical evidence for the potential involvement of glial cells in neuropathic pain conditions. Several glial-targeted agents are in development for the treatment of pain conditions. Here we report the failure of a glial modulating agent, propentofylline, to decrease pain reported in association with post-herpetic neuralgia. ⋯ Overall, human microglia were less responsive to LPS stimulation and propentofylline treatment than the other cell types. Our data demonstrate significant functional differences between cell types and species following propentofylline treatment and LPS stimulation. These results may help explain the differential behavioral effects of propentofylline observed between rodent models of pain and the human clinical trial.
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Experimental neurology · Apr 2012
Prostaglandin E2 contributes to the synthesis of brain-derived neurotrophic factor in primary sensory neuron in ganglion explant cultures and in a neuropathic pain model.
Brain-derived neurotrophic factor (BDNF) exists in small to medium size neurons in adult rat dorsal root ganglion (DRG) and serves as a modulator at the first synapse of the pain transmission pathway in the spinal dorsal horn. Peripheral nerve injury increases BDNF expression in DRG neurons, an event involved in the genesis of neuropathic pain. In the present study, we tested the hypothesis that prostaglandin E2 (PGE2) over-produced in injured nerves contributes to the up-regulation of BDNF in DRG neurons. ⋯ Taken together, EP1 and EP4 receptor subtypes, PKA, ERK/MAPK and CREB signaling pathways as well as NGF are involved in PGE2-induced BDNF synthesis in DRG neurons. Injured nerve derived-PGE2 contributes to BDNF up-regulation in DRG neurons following nerve injury. Facilitating the synthesis of BDNF in primary sensory neurons is a novel mechanism underlying the role of PGE2 in the genesis of neuropathic pain.
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Experimental neurology · Apr 2012
Increased atypical PKC expression and activity in the phrenic motor nucleus following cervical spinal injury.
Atypical protein kinase C (aPKC) isoforms are expressed in phrenic motor neurons, a group of motor neurons critical for breathing. Following C2 cervical hemisection (C2HS), spontaneous plasticity occurs in crossed-spinal synaptic pathways to phrenic motor neurons, at least partially restoring inspiratory phrenic activity below the injury. Since aPKCs are necessary for synaptic plasticity in other systems, we tested the hypothesis that C2HS increases aPKC expression and activity in spinal regions associated with the phrenic motor nucleus. ⋯ Ipsilateral aPKC activity and expression were strongly correlated (r(2)=0.675, p<0.001). In a distinct group of rats, immunohistochemistry confirmed that aPKCs are expressed in neurons 28 days post-C2HS, including large, presumptive phrenic motor neurons; aPKCs were not detected in adjacent microglia (OX-42 positive cells) or astrocytes (GFAP positive cells). Changes in aPKC expression in the phrenic motor nucleus following C2HS suggests that aPKCs may contribute to functional recovery following cervical spinal injury.
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Experimental neurology · Apr 2012
Peri-sciatic administration of recombinant rat IL-1β induces mechanical allodynia by activation of src-family kinases in spinal microglia in rats.
Previous studies have shown that Interleukin-1 beta (IL-1β) is implicated in the modulation of pain sensitivity. In the present study, we found that a single peri-sciatic administration of rat recombinant IL-1β (rrIL-1β) at doses of 20 and 200 pg (100, 1000 ng/l, in 200 μl volume) induced mechanical allodynia in bilateral hindpaws in rats, lasting for about 50 days. No axonal or Schwann cell damage at the drug administration site was found following 1000 ng/l rrIL-1β administration. ⋯ Intrathecal delivery of minocycline (100 μg in 10 μl volume), a selective inhibitor of microglia, started 30 min before rrIL-1β administration and once daily thereafter for 7 days, blocked mechanical allodynia induced by rrIL-1β completely and inhibited the upregulation of p-SFKs. Intrathecal delivery of SFKs inhibitor PP2 (12 μg in 10 μl volume) also blocked mechanical allodynia induced by rrIL-1β completely. These data suggest that activation of SFKs in spinal microglia mediates mechanical allodynia induced by peri-sciatic administration of rrIL-1β.