Biomedical subjects

Leah Spataro

Publications and source records attributed to Leah Spataro.

3 recordsLinked to original sources

PubMed2005

Controlling neuropathic pain by adeno-associated virus driven production of the anti-inflammatory cytokine, interleukin-10.

Despite many decades of drug development, effective therapies for neuropathic pain remain elusive. The recent recognition of spinal cord glia and glial pro-inflammatory cytokines as important contributors to neuropathic pain suggests an alternative therapeutic strategy; that is, targeting glial activation or its downstream consequences. While several glial-selective drugs have been successful in controlling neuropathic pain in animal models, none are optimal for human use. Thus the aim of the present studies was to explore a novel approach for controlling neuropathic pain. Here, an adeno-associated viral (serotype II; AAV2) vector was created that encodes the anti-inflammatory cytokine, interleukin-10 (IL-10). This anti-inflammatory cytokine is known to suppress the production of pro-inflammatory cytokines. Upon intrathecal administration, this novel AAV2-IL-10 vector was successful in transiently preventing and reversing neuropathic pain. Intrathecal administration of an AAV2 vector encoding beta-galactosidase revealed that AAV2 preferentially infects meningeal cells surrounding the CSF space. Taken together, these data provide initial support that intrathecal gene therapy to drive the production of IL-10 may prove to be an efficacious treatment for neuropathic pain.

Animals↗

PubMed2004

HIV-1 gp120 stimulates proinflammatory cytokine-mediated pain facilitation via activation of nitric oxide synthase-I (nNOS).

It has become clear that spinal cord glia (microglia and astrocytes) importantly contribute to the creation of exaggerated pain responses. One model used to study this is peri-spinal (intrathecal, i.t.) administration of gp120, an envelope protein of HIV-1 known to activate glia. Previous studies demonstrated that i.t. gp120 produces pain facilitation via the release of glial proinflammatory cytokines. The present series of studies tested whether spinal nitric oxide (NO) contributes to i.t. gp120-induced mechanical allodynia and, if so, what effect NO has on spinal proinflammatory cytokines. gp120 stimulation of acutely isolated lumbar dorsal spinal cords released NO as well as proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta (IL1), interleukin-6 (IL6)), thus identifying NO as a candidate mediator of gp120-induced behavioral effects. Behaviorally, identical effects were observed when gp120-induced mechanical allodynia was challenged by i.t. pre-treatment with either a broad-spectrum nitric oxide synthase (NOS) inhibitor (L-NAME) or 7-NINA, a selective inhibitor of NOS type-I (nNOS). Both abolished gp120-induced mechanical allodynia. While the literature pre-dominantly documents that proinflammatory cytokines stimulate the production of NO rather than the reverse, here we show that gp120-induced NO increases proinflammatory cytokine mRNA levels (RT-PCR) and both protein expression and protein release (serial ELISA). Furthermore, gp120 increases mRNA for IL1 converting enzyme and matrix metalloproteinase-9, enzymes responsible for activation and release of proinflammatory cytokines.

Animals↗

PubMed2003

Controlling cellular reactive responses around neural prosthetic devices using peripheral and local intervention strategies.

While chronic use of indwelling micromachined neural prosthetic devices has great potential, the development of reactive responses around them results in a decrease in electrode function over time. Since the cellular events responsible for these responses may be anti-inflammatory in nature, we have tested the effectiveness of dexamethasone and cyclosporin A as potential drugs for developing intervention strategies following insertion of single-shank micromachined silicon devices. Peripheral injection of dexamethasone was effective in attenuating increased expression of glial fibrillary acidic protein and astrocyte hyperplasia observed during both initial- and sustained-reactive responses observed at one and six weeks post insertion, respectively. Peripheral injection of cyclosporin A had no positive effect. If anything, application of this drug increased the early reactive response. Effectiveness of local release of dexamethasone in rat neocortex was tested by inserting ribbons of poly (ethyl-vinyl) acetate containing 35% (w/w) dexamethasone. Initial concentrations of dexamethasone were similar to those obtained by peripheral injection. Local drug release provided continued control of cellular reactive responses during the six-week study period. These results demonstrate that peripheral delivery of dexamethasone can be used to control reactive responses and that local drug delivery by slow-release from biocompatible polymers may be a more effective method of drug intervention. Incorporating these strategies on micromachined devices may provide an intervention strategy that will insure the chronic functioning of electrodes on intracortical neuroprosthetic devices.

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