Nanoparticles may reduce impact of neurological injury [PreClinical]

1. Squalenoyl adenosine nanoassemblies (SQAdNAs) formed by conjugating squalene, a lipid, to adenosine, a widely regarded potential neuroprotective agent, resulted in delayed metabolism of SQAdNAs as compared to immediate metabolism of adenosine.

2. Injection of SQAdNAs reduced the impacts of cerebral ischemia in mice and spinal cord injury (SCI) in rats.

Evidence Rating Level: 2 (Good)

Study Rundown: Acute neurological injuries, including stroke and SCI, often have lifelong debilitating effects on mental cognition and physical function. Drugs administered to limit these effects, such as adenosine, have met limited success due to their rapid clearance from the bloodstream.

Here, researchers developed SQAdNAs by covalently conjugating the lipid squalene to adenosine. They showed that significant amounts of SQAdNAs remained intact in mouse blood 60 minutes post injection, while free adenosine was undetectable after one minute. A mouse model of cerebral ischemia showed that pre- or post-ischemic injection of SQAdNAs significantly reduced the cerebral infarct size and neurological deficit score in animals as compared to controls. This result held with or without reperfusion of the ischemic area. In a second study, SQAdNA injection within 5 minutes of rat SCI resulted in significantly improved locomotion and less visible cord trauma at 72 hours post-injury as compared to controls. Nine days post-injury, treated animals advanced into late phases of recovery, a stage not reached by control animals even at the end of assessment (28 days). The researchers also demonstrated that SQAdNAs did not cause appetite loss and sleep cycle alterations commonly observed with adenosine treatment, and appeared to be non-toxic.

The preemptive (pre-ischemia) and early (5 minutes post-SCI) SQAdNA administration and extensive neurological damage in most of these experiments limit their applicability to human stroke and SCI, which are often detected hours after occurrence and are less massive in scale. Further delayed-administration studies will shed light on the utility of SQAdNAs for such cases. This study suggests nanoparticles of covalently linked lipid and adenosine molecules may prolong adenosine circulation and be used to effectively treat human neurological injuries.

Click to read the study in Nature Nanotechnology 

Relevant Reading: Adenosine as a neuromodulator in neurological diseases

In-Depth [animal study]: SQAdNAs measuring ~120 nm in diameter were formed by spontaneous nanoprecipitation of synthesized squalenoyl adenosine, which was created through covalent linkage of adenosine and squalenylacetic acid. SQAdNAs incubated with mouse plasma for several hours were physically stable, as shown with dynamic light scattering, and chemically stable, as shown with high performance liquid chromatography (HPLC). HPLC measurements also showed that approximately one fourth of SQAdNAs detected immediately post injection remained in mouse blood 60 minutes later, while free adenosine was undetectable after one minute.

In a mouse model of cerebral infarction, infarct size was reduced from 49±1 mm3 in dextrose-treated control mice to 17±1 mm3 in mice injected with 15 mg/kg of SQAdNAs pre-ischemia (equivalent to 5.5 mg/kg adenosine; N=6 mice/group; p<0.05). Adenosine-only or squalenoyl-only nanoassembly treatment mice demonstrated similar infarct sizes to the dextrose control group. Mice that received an injection of 15 mg/kg SQAdNA 2 hours post stroke demonstrated significantly smaller sized infarcts when compared to vehicle control mice. This was true whether perfusion was administered 2 hours post stroke or not. Neurological deficit scores measured animal motor activity, and were lower in all SQAdNA groups as compared to corresponding controls (p<0.05).

The Basso, Beattie and Bresnahan (BBB) scale was used to measure locomotion changes for a rat SCI model treated with 32 mg/kg of SQAdNAs in comparison to dextrose, adenosine, and squalenoyl nanoassemblies controls (N=10 rats/group). At 48 hours post-SCI, SQAdNA-treated rats had higher BBB scores than control rats (p<0.05), an effect that was increasingly marked at 72 hours (p<0.01), 5 days (p<0.001) and 9-28 days (p<0.0001). Animals given SQAdNAs ingested similar food quantities to dextrose-treated animals (N=10 animals/group), and did not differ significantly in their REM sleep quantities throughout the day (N=15 animals/group). No significant differences in various blood counts or histological analyses were found between SQAdNA and dextrose-treated animals.

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Image: PD

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