Status Epilepticus due to Intraperitoneal Injection of Vehicle Containing Propylene Glycol in Sprague Dawley Rats

Published reports of status epilepticus due to intraperitoneal injection containing propylene glycol in rats are sparse. In fact, there are no reports specifying a maximum safe dose of propylene glycol through intraperitoneal administration. We report here a case of unexpected seizures in Sprague Dawley rats after receiving an intraperitoneal injection containing propylene glycol. Nine-week-old, 225–250 gram male rats were reported to experience tremor progressing to seizures within minutes after given injections of resveratrol (30 mg/kg) dissolved in a 40 : 60 propylene glycol/corn oil vehicle solution by direct intraperitoneal (IP) slow bolus injection or via a preplaced intraperitoneal catheter. The World Health Organization suggests a maximum dose of 25 mg/kg/day of propylene glycol taken orally and no more than 25 mg/dL in blood serum, whereas the animals used in our study got a calculated maximum 0.52 g/kg (25 times lower dose). Blood tests from the seizing rat support a diagnosis of hemolysis and lactic acidosis which may have led to the seizures, all of which appeared to be a consequence of the propylene glycol administration. These findings are consistent with oral and intravenous administration of propylene glycol toxicity as previously reported in other species, including humans. To our knowledge, this report represents the first published case of status epilepticus due to an IP injection containing propylene glycol

Implantation of Neural Probes in the Brain Elicits Oxidative Stress

Clinical implantation of intracortical microelectrodes has been hindered, at least in part, by the perpetual inflammatory response occurring after device implantation. The neuroinflammatory response observed after device implantation has been correlated to oxidative stress that occurs due to neurological injury and disease. However, there has yet to be a definitive link of oxidative stress to intracortical microelectrode implantation. Thus, the objective of this study is to give direct evidence of oxidative stress following intracortical microelectrode implantation. This study also aims to identify potential molecular targets to attenuate oxidative stress observed postimplantation. Here, we implanted adult rats with silicon non-functional microelectrode probes for 4 weeks and compared the oxidative stress response to no surgery controls through postmortem gene expression analysis and qualitative histological observation of oxidative stress markers. Gene expression analysis results at 4 weeks postimplantation indicated that EH domain-containing 2, prion protein gene (Prnp), and Stearoyl-Coenzyme A desaturase 1 (Scd1) were all significantly higher for animals implanted with intracortical microelectrode probes compared to no surgery control animals. To the contrary, NADPH oxidase activator 1 (Noxa1) relative gene expression was significantly lower for implanted animals compared to no surgery control animals. Histological observation of oxidative stress showed an increased expression of oxidized proteins, lipids, and nucleic acids concentrated around the implant site. Collectively, our results reveal there is a presence of oxidative stress following intracortical microelectrode implantation compared to no surgery controls. Further investigation targeting these specific oxidative stress linked genes could be beneficial to understanding potential mechanisms and downstream therapeutics that can be utilized to reduce oxidative stress-mediated damage following microelectrode implantation

Investigation of the Feasibility of Ventricular Delivery of Resveratrol to the Microelectrode Tissue Interface

(1) Background: Intracortical microelectrodes (IMEs) are essential to basic brain research and clinical brain–machine interfacing applications. However, the foreign body response to IMEs results in chronic inflammation and an increase in levels of reactive oxygen and nitrogen species (ROS/RNS). The current study builds on our previous work, by testing a new delivery method of a promising antioxidant as a means of extending intracortical microelectrodes performance. While resveratrol has shown efficacy in improving tissue response, chronic delivery has proven difficult because of its low solubility in water and low bioavailability due to extensive first pass metabolism. (2) Methods: Investigation of an intraventricular delivery of resveratrol in rats was performed herein to circumvent bioavailability hurdles of resveratrol delivery to the brain. (3) Results: Intraventricular delivery of resveratrol in rats delivered resveratrol to the electrode interface. However, intraventricular delivery did not have a significant impact on electrophysiological recordings over the six-week study. Histological findings indicated that rats receiving intraventricular delivery of resveratrol had a decrease of oxidative stress, yet other biomarkers of inflammation were found to be not significantly different from control groups. However, investigation of the bioavailability of resveratrol indicated a decrease in resveratrol accumulation in the brain with time coupled with inconsistent drug elution from the cannulas. Further inspection showed that there may be tissue or cellular debris clogging the cannulas, resulting in variable elution, which may have impacted the results of the study. (4) Conclusions: These results indicate that the intraventricular delivery approach described herein needs further optimization, or may not be well suited for this application

Investigating the Association between Motor Function, Neuroinflammation, and Recording Metrics in the Performance of Intracortical Microelectrode Implanted in Motor Cortex

Long-term reliability of intracortical microelectrodes remains a challenge for increased acceptance and deployment. There are conflicting reports comparing measurements associated with recording quality with postmortem histology, in attempts to better understand failure of intracortical microelectrodes (IMEs). Our group has recently introduced the assessment of motor behavior tasks as another metric to evaluate the effects of IME implantation. We hypothesized that adding the third dimension to our analysis, functional behavior testing, could provide substantial insight on the health of the tissue, success of surgery/implantation, and the long-term performance of the implanted device. Here we present our novel analysis scheme including: (1) the use of numerical formal concept analysis (nFCA) and (2) a regression analysis utilizing modern model/variable selection. The analyses found complimentary relationships between the variables. The histological variables for glial cell activation had associations between each other, as well as the neuronal density around the electrode interface. The neuronal density had associations to the electrophysiological recordings and some of the motor behavior metrics analyzed. The novel analyses presented herein describe a valuable tool that can be utilized to assess and understand relationships between diverse variables being investigated. These models can be applied to a wide range of ongoing investigations utilizing various devices and therapeutics

Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia

Ischemia exists in many diseased tissues, including arthritic joints, atherosclerotic plaques, and malignant tumors. Macrophages accumulate in these sites and up-regulate hypoxia-inducible transcription factors (HIFs) 1 and 2 in response to the hypoxia present. Here we show that the gene expression profile in primary human and murine macrophages changes markedly when they are exposed to hypoxia for 18 hours. For example, they were seen to up-regulate the cell surface receptors, CXCR4 and GLUT1, and the potent, tumor-promoting cytokines, vascular endothelial growth factor A, interleukin (IL)-1 beta and IL-8, adrenomedullin, CXCR4, and angiopoietin-2. Hypoxia also stimulated their expression and/or phosphorylation of various proteins in the nuclear factor-kappa B (NF-kappa B) signaling pathway. We then used both genetic and pharmacologic methods to manipulate the levels of HIFs-1 alpha and 2 alpha or NF-kappa B in primary macrophages to elucidate their role in the hypoxic induction of many of these key genes. These studies showed that both HIF-1 and -2, but not NF-kappa B, are important transcriptional effectors regulating the responses of macrophages to such a period of hypoxia. Further studies using experimental mouse models are now warranted to investigate the role of such macrophage responses in the progression of various diseased tissues, such as malignant tumors. (Blood. 2009; 114: 844-859