Functional and Structural Improvement with a Catalytic Carbon Nano-Antioxidant in Experimental Traumatic Brain Injury Complicated by Hypotension and Resuscitation

Abstract

Hypotension worsens outcome after all severities of traumatic brain injury (TBI), with loss of cerebral autoregulation being a potential contributor. Previously, we demonstrated that intravenous injection of a high capacity catalytic antioxidant, poly(ethylene)glycol conjugated hydrophilic carbon clusters (PEG-HCCs) rapidly restored cerebral perfusion and acutely restored brain oxidative balance in a TBI model complicated by hemorrhagic hypotension without evidence of toxicity. Here, we tested whether these acute effects translated into behavioral and structural benefit. TBI was generated by a cortical contusion impactor in 38 Long Evans rats, followed by blood withdrawal to a target mean arterial pressure of 40 mm Hg. PEG-HCC (2 mg/kg) or diluent was injected intravenously 80 min later at the onset of blood resuscitation followed by another injection 2 h later (doses determined in prior studies). Performance on beam walking (performed on days 1-5) and Morris water maze (MWM) (performed on days 11-15) was tested, and lesion size was determined at the termination. PEG-HCC treatment nearly completely prevented motor dysfunction (p < 0.001 vs. diluent), improved MWM performance (p < 0.001; treatment vs. time interaction) and reduced lesion size by 61% (p = 0.054). Here we show that treatment with PEG-HCCs at a clinically realistic time point (onset of resuscitation) prevented a major portion of the neurological dysfunction induced in this TBI model, and that PEG-HCCs are candidates for additional study as a potential therapeutic agent.

Pervasive Genomic Damage in Experimental Intracerebral Hemorrhage: Therapeutic Potential of a Mechanistic-Based Carbon Nanoparticle

“…We tested the effectiveness of DEF-HCC-PEG on hemin-treated neurons and in an experimental ICH mouse model. The concentration and dose of DEF-HCC-PEG were guided by our prior work with PEG-HCCs. , The DEF-HCC-PEG treatment restored viability of hemin-treated cells at a significantly higher efficiency compared to PEG-HCC or DEF treatment alone (Figure b). DEF-HCC-PEG treatment also strongly reduced the levels of DNA damage markers γH2AX and p-53BP1 compared to DEF or PEG-HCC treatment (Figure c,d).…”

Multifunctional Nanoparticles and Nanoclusters as a Theranostics and Symptoms Disappearing Agent for Traumatic Brain Injury

“…[82] PEG-HCCs treatment has also been shown in subsequent studies to be effective in reducing ischemia-induced infarct size, brain swelling, and hemorrhage and improving functional deficit in a rat model of MCAO with acute hyperglycemia [88] and experimental CCI rat model complicated by hypotension at the onset of blood resuscitation. [89] Additionally, the highly stable PEG-HCC can also be further functionalized with additional targeting moieties such as antibodies and targeting peptides for targeted drug delivery without losing its antioxidative properties. [90][91][92] In 2020, PEG-HCC was conjugated to deferoxamine (DEF) to formulate a multifunctional therapeutic NP (PEG-HCC-DEF) that can be used as a combinatorial therapy for ICH.…”

Nanomaterials alleviating redox stress in neurological diseases: mechanisms and applications

“…In a model of reversible middle cerebral artery stroke, PEG-HCCs can rapidly restore cerebral perfusion and acutely restore brain oxidative balance without evidence of toxicity [ 94 ]. PEG-HCCs were found to have similar neuroprotective effects in a TBI model [ 103 ]. Interestingly, a newly discovered carbogenic nanozyme was highly selective in scavenging RNS (Fig.…”