An optimized dosing regimen of cimaglermin (neuregulin 1β3, glial growth factor 2) enhances molecular markers of neuroplasticity and functional recovery after permanent ischemic stroke in rats

Abstract

Cimaglermin (neuregulin 1b3, glial growth factor 2) is a neuregulin growth factor family member in clinical development for chronic heart failure. Previously, in a permanent middle cerebral artery occlusion (pMCAO) rat stroke model, systemic cimaglermin treatment initiated up to 7 days after ischemia onset promoted recovery without reduced lesion volume. Presented here to extend the evidence are two studies that use a rat stroke model to evaluate the effects of cimaglermin dose level and dose frequency initiated 24 hr after pMCAO. Forelimb-and hindlimb-placing scores (proprioceptive behavioral tests), body-swing symmetry, and infarct volume were compared between treatment groups (n 5 12/group). Possible mechanisms underlying cimaglermin-mediated neurologic recovery were examined through axonal growth and synapse formation histological markers. Cimaglermin was evaluated over a wider dose range (0.02, 0.1, or 1.0 mg/kg) than doses previously shown to be effective but used the same dosing regimen (2 weeks of daily intravenous administration, then 1 week without treatment). The dose-frequency study used the dose-ranging study's most effective dose (1.0 mg/kg) to compare daily, once per week, and twice per week dosing for 3 weeks (then 1 week without treatment). Dose-and frequency-dependent functional improvements were observed with cimaglermin without reduced lesion volume. Cimaglermin treatment significantly increased growth-associated protein 43 expression in both hemispheres (particularly somatosensory and motor cortices) and also increased synaptophysin expression. These data indicate that cimaglermin enhances recovery after stroke. Immunohistochemical changes were consistent with axonal sprouting and synapse formation but not acute neuroprotection. Cimaglermin represents a potential clinical development candidate for ischemic stroke treatment. Early results with cimaglermin, a neuregulin isoform, demonstrated functional improvements when initiated up to 7 days after middle cerebral artery occlusion in preclinical animal models of stroke. The studies presented here extend these observations to show that functional improvements in a rat stroke model using cimaglermin initiated within a 24-hr poststroke window are dose and frequency dependent, with 1 mg/kg cimaglermin significantly improving all functional measures vs. vehicle. Results from markers of new neuronal axon growth and contact formation were consistent with promoting neurologic recovery.

Inosine enhances recovery of grasp following cortical injury to the primary motor cortex of the rhesus monkey

“…Recovery that has been found appears to correlate with a variety of mechanistic processes including dendritic remodeling, synaptogenesis, axonal sprouting and angiogenesis in peri-infarct regions. Nevertheless, our understanding of the mechanisms underlying re-organization and plasticity still remains unclear but points to plasticity within these areas as a target for therapeutic intervention (Carmichael et al, 2016; Iaci et al, 2016; Liu & Chopp, 2015; Meng et al, 2014; Barratt et al, 2014; Nouri & Cramer, 2011; Benowitz & Carmichael, 2010; Iaci et al, 2010; Benowitz & Carmichael, 2010; Beck & Plate, 2009; Zhang & Chopp, 2009; Cramer, 2008a,b, 2011; Buga et al, 2008; Carmichael, 2006; Li & Carmichael, 2006; Hayashi et al, 2003; Carmichael & Chesselet, 2002; Beck et al, 2000; Marti et al, 2000; Stroemer et al, 1998; Benowitz & Routtenberg, 1997). Indeed, a variety of agents that promote plasticity have enhanced functional recovery in rodent models of ischemic stroke (Duricki et al, 2016; George & Steinberg, 2015; Chollet et al, 2014; Dachir et al, 2014; Dhawan et al, 2011; Zai et al, 2009; Papadopoulos, 2009).…”

Neuregulin in Health and Disease

“…Cimaglermin (NRG-1β) treatment significantly enhanced recovery after stroke, inducing axonal sprouting and synapse formation. These data suggested that Cimaglermin represents a potential candidate for stroke treatment [115].…”

Neuroprotection by Exogenous and Endogenous Neuregulin-1 in Mouse Models of Focal Ischemic Stroke

“…NRG-1 administration Jessica Noll and Yonggang Li contributed equally to this work. resulted in a significant improvement of neurological function when administered 3 days following ischemia, suggesting a role in neuronal repair (Iaci et al 2010(Iaci et al , 2016. Recent clinical studies demonstrated the utility of NRG-1 in human patients (Gao et al 2010;Jabbour et al 2011;Lenihan et al 2016) ( C l i n i c a l Tr i a l s .…”