Neuroinflammation and Cerebrovascular Disease in Old Age: A Translational Medicine Perspective
Table 1
Neuroprotective agents targeting neuroinflammation in acute stroke.
Neuroprotective agent
Mode of action
Summary of clinical trials
Recombinant human IL-1 ra (rhIL-1ra)
Interleukin-1 receptor antagonist
In the phase II clinical trial of rhIL-1ra, patients within 6 hours of stroke symptom onset were randomised to either rhIL-1ra or placebo. In the rhIL-1ra-treated group, patients with cortical infarcts had a better clinical outcome [45].
Enlimomab
Anti-ICAM -1 monoclonal antibody
In the phase III clinical trial of enlimomab, patients were randomised to receive either the monoclonal antibody or placebo within 6 hours of acute stroke onset. The modified Rankin scale was worse in patients treated with enlimomab (), and treatment was associated with higher mortality. Further development of this drug has been abandoned [28].
UK-279, 276
Neutrophil inhibitory factor
In the Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN) phase II clinical trial, patients were randomised to receive either an infusion of UK-279, 276, or placebo within 6 hours of acute stroke symptom onset. No efficacy was reported on administration of study medication, and the clinical trial was terminated for futility [48].
Cerovive (NXY-059)
Nitrone-based free radical trapping agent
In the phase III clinical trial, Stroke-Acute Ischemic—NXY-059 Treatment II (SAINT II) randomised patients within 6 hours of acute stroke onset to either an infusion of NXY-059 or placebo. There was no significant reduction in stroke-related disability, as assessed by the modified Rankin scale (). The Cerebral Hemorrhage And NXY-059 Treatment (CHANT) trial also showed no treatment effect on functional outcome. Further drug development has been abandoned [49, 50].
Edaravone (Radicut)
Free radical scavenger
Lacunar stroke patients treated with edaravone showed significant reduction in infarct size at 1-year followup and early improved neurological outcomes. There was no difference in overall clinical outcomes after 1 year [51, 52].
Uric acid
Antioxidant
The phase II double-blinded study investigated safety and pharmacokinetics of uric acid in acute stroke patients treated with rt-PA. Levels of uric acid increased in the treatment group, with reduction in lipid peroxidation. No safety concerns were reported with uric acid treatment. Further evaluation is ongoing [53, 54].
Acetaminophen (Paracetamol)
Antipyretic effect
In the Paracetamol (Acetaminophen) in Stroke (PAIS) clinical trial, patients presenting within 12 hours of acute stroke onset were randomised to either acetaminophen (6 g daily) or placebo for three days. There was no benefit seen for routine use of acetaminophen in acute stroke but post hoc analysis showed beneficial effects in patients with body temperature between 37 and 39°C [55].
Stroke patients with NIHSS > 5 and symptom onset between 6 and 24 hours were randomised to either once daily minocycline 200 mg or placebo for 5 days. The NIHSS and modified Rankin scale were significantly lower in the treatment group at 90 days [56].
The Minocycline to Improve Neurologic Outcome in Stroke (MINOS) study was a dose-escalation trial, administering intravenous minocycline within 6 hours of symptom onset. This was shown to be safe and well tolerated up to 10 mg/kg intravenous dosing [57].
