A caution to brain scientists: unsuspected hemorrhagic vascular damage resulting from mere electrode implantation

Boast, Carl A.; Reid, Scott D.; Johnson, Paul A.; Zornetzer, Steven F.

doi:10.1016/0006-8993(76)90450-9

Cited by 36 publications

(8 citation statements)

References 23 publications

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“…This, however, would significantly increase the effort associated with such experiments and may also affect the outcome of drug experiments, because chronic seizure monitoring is associated with distress and discomfort, particularly in mice. Furthermore, implantation of EEG electrodes in rodents (and patients) is known to be associated with brain alterations, including inflammation, hemorrhage, blood–brain barrier dysfunction, and neuronal dysfunction . Substantial inflammation and compromised blood–brain barrier occur even in response to bone screw electrodes that do not penetrate into the brain .…”

Section: Discussionmentioning

confidence: 99%

The bumetanide prodrug BUM5, but not bumetanide, potentiates the antiseizure effect of phenobarbital in adult epileptic mice

Erker

Brandt²,

Töllner³

et al. 2016

Epilepsia

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SUMMARYObjective: The loop diuretic bumetanide has been reported to potentiate the antiseizure activity of phenobarbital in rodent models of neonatal seizures, most likely as a result of inhibition of the chloride importer Na-K-Cl cotransporter isoform 1 (NKCC1) in the brain. In view of the intractability of neonatal seizures, the preclinical findings prompted a clinical trial in neonates on bumetanide as an add-on to phenobarbital, which, however, had to be terminated because of ototoxicity and lack of efficacy. We have recently shown that bumetanide penetrates only poorly into the brain, so that we developed lipophilic prodrugs such as BUM5, the N,N-dimethylaminoethylester of bumetanide, which penetrate more easily into the brain and are converted to bumetanide. Methods: In the present study, we used a new strategy to test whether BUM5 is more potent than bumetanide in potentiating the antiseizure effect of phenobarbital. Adult mice were made epileptic by pilocarpine, and the antiseizure effects of bumetanide, BUM5, and phenobarbital alone or in combination were determined by the maximal electroshock seizure threshold test. Results: In nonepileptic mice, only phenobarbital exerted seizure threshold-increasing activity, and this was not potentiated by the NKCC1 inhibitors. In contrast, a marked potentiation of phenobarbital by BUM5, but not bumetanide, was determined in epileptic mice. Significance: Thus, bumetanide is not capable of potentiating phenobarbital's antiseizure effect in an adult mouse model, which, however, can be overcome by using the prodrug BUM5. These data substantiate that BUM5 is a promising tool compound for target validation and proof-of-concept studies on the role of NKCC1 in brain diseases.

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Section: Discussionmentioning

confidence: 99%

The bumetanide prodrug BUM5, but not bumetanide, potentiates the antiseizure effect of phenobarbital in adult epileptic mice

Erker

Brandt²,

Töllner³

et al. 2016

Epilepsia

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“…Age (Dube et al, 2001; Priel et al, 1996; Sankar et al, 1997), strain (Xu et al, 2004), pilocarpine dose (Cavalheiro et al, 1987; Priel et al, 1996), presence of lithium (Clifford et al, 1987), electrode implantation techniques (Boast et al, 1976; Loscher et al, 1995), attenuation of SE with benzodiazepine (Hasson et al, 2008) or paraldehyde (Kubova et al, 2005), as well as both timing and type of injury assessment have all been postulated to affect the degree of detectable neuronal loss. Table 2 summarizes some of the parameters used previously to assess for neuronal damage outside the hippocampus in immature animals after LiPC induced SE (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Neuronal degeneration is observed in multiple regions outside the hippocampus after lithium pilocarpine-induced status epilepticus in the immature rat

2013

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Although hippocampal sclerosis is frequently identified as a possible epileptic focus in patients with temporal lobe epilepsy, neuronal loss has also been observed in additional structures, including areas outside the temporal lobe. The claim from several researchers using animal models of acquired epilepsy that the immature brain can develop epilepsy without evidence of hippocampal neuronal death raises the possibility that neuronal death in some of these other regions may also be important for epileptogenesis. The present study used the lithium pilocarpine model of acquired epilepsy in immature animals to assess which structures outside the hippocampus are injured acutely after status epilepticus. Sprague Dawley rat pups were implanted with surface EEG electrodes, and status epilepticus was induced at 20 days of age with lithium pilocarpine. After 72 h, brain tissue from 12 animals was examined with Fluoro-Jade B, a histochemical marker for degenerating neurons. All animals that had confirmed status epilepticus demonstrated Fluoro-Jade B staining in areas outside the hippocampus. The most prominent staining was seen in thalamus (mediodorsal, paratenial, reuniens, and ventral lateral geniculate nuclei), amygdala (ventral lateral, posteromedial, and basomedial nuclei), ventral premammillary nuclei of hypothalamus, and paralimbic cortices (perirhinal, entorhinal, and piriform) as well as parasubiculum and dorsal endopiriform nuclei. These results demonstrate that lithium pilocarpine-induced status epilepticus in the immature rat brain consistently results in neuronal injury in several distinct areas outside of the hippocampus. Many of these regions are similar to areas damaged in patients with temporal lobe epilepsy, thus suggesting a possible role in epileptogenesis.

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“…For example, surgical insertion of implants (e.g., neural probes) leads to a temporary disruption of blood vessels [35], possibly resulting in release of serum HAase (~2.6 U mL -1 in human serum) [34]. Thus, it is possible that the electrodes’ ability to prevent cell attachment and migration in vivo can be impaired.…”

Section: Resultsmentioning

confidence: 99%

Pyrrole–hyaluronic acid conjugates for decreasing cell binding to metals and conducting polymers

Lee

Schmidt

2010

Acta Biomaterialia

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Surface modification of electrically conductive biomaterials has been studied to improve biocompatibility for a number of applications, such as implantable sensors and microelectrode arrays. In this study, we electrochemically coated electrodes with biocompatible and non-cell adhesive hyaluronic acid (HA) to reduce cellular adhesion for potential use in neural prostheses. To this end, pyrrole-conjugated hyaluronic acid (PyHA) was synthesized and employed for electrochemical coating of platinum, indium-tin-oxide, and polystyrene sulfonate-doped polypyrrole electrodes. This PyHA conjugate consists of (1) a pyrrole moiety that allows the compound to be electrochemically deposited onto a conductive substrate and (2) non-adhesive HA to minimize cell adhesion and to potentially decrease inflammatory tissue responses. Our characterization results showed the presence of a hydrophilic p(PyHA) layer on the modified electrode, and impedance measurements revealed impedance that was statistically the same as the unmodified electrode. We found that the p(PyHA)-coated electrodes minimized adhesion and migration of fibroblasts and astrocytes for a minimum of up to 3 months. Also, the coating was stable in physiological solution for 3 months and also stable against enzymatic degradation by hyaluronidase. These studies suggest that this p(PyHA)-coating has the potential to be used to mask conducting electrodes from adverse glial responses that occur upon implantation. In addition, electrochemical coating with PyHA can be potentially extended for the surface modification of other metallic and conducting substances such as stents and biosensors.

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A caution to brain scientists: unsuspected hemorrhagic vascular damage resulting from mere electrode implantation

Cited by 36 publications

References 23 publications

The bumetanide prodrug BUM5, but not bumetanide, potentiates the antiseizure effect of phenobarbital in adult epileptic mice

The bumetanide prodrug BUM5, but not bumetanide, potentiates the antiseizure effect of phenobarbital in adult epileptic mice

Neuronal degeneration is observed in multiple regions outside the hippocampus after lithium pilocarpine-induced status epilepticus in the immature rat

Pyrrole–hyaluronic acid conjugates for decreasing cell binding to metals and conducting polymers

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