Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Abstract

Tissue plasminogen activator is the only treatment option for stroke victims; however, it has to be administered within 4.5 h after symptom onset, making its use very limited. This report describes a unique target for effective treatment of stroke, even 12 h after onset, by the administration of αB-crystallin (Cryab), an endogenous immunomodulatory neuroprotectant. In Cryab −/− mice, there was increased lesion size and diminished neurologic function after stroke compared with wild-type mice. Increased plasma Cryab was detected after experimental stroke in mice and after stroke in human patients. Administration of Cryab even 12 h after experimental stroke reduced both stroke volume and inflammatory cytokines associated with stroke pathology. Cryab is an endogenous anti-inflammatory and neuroprotectant molecule produced after stroke, whose beneficial properties can be augmented when administered therapeutically after stroke.

Chaperone Activity of Small Heat Shock Proteins Underlies Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis

“…The anti-inflammatory property was not due to influencing the adaptive immune response directly, but rather there was binding and resultant modulation of the proinflammatory mediators in plasma (29). These observations are at the basis of the therapeutic effects seen in both autoimmune and ischemic models of disease, including EAE, stroke, myocardial infarction, and retinal ischemia (25)(26)(27)(28).…”

“…This was true in both HspB5 knock-out and wild-type mice. Subsequent studies have demonstrated that HspB5 is effective in reducing the lesion size in a murine model of stroke (26), reducing inflammation and improving heart function in a model of myocardial infarction (27) and increased oligodendroglial survival in the optic nerve in a model of retinal ischemia (28). Further analyses in these animal models concluded that the protein was immunosuppressive.…”

Beneficial Effects of αB-Crystallin in Spinal Cord Contusion Injury

“…This dose was previously shown to be effective in EAE and stroke (Ousman et al, 2007;Arac et al, 2011). The total amount of endotoxins administrated intravenously per mouse was 0.5 EU/kg body weight/d, lower than the maximum endotoxin levels set by the FDA for injectable drugs (5 EU/kg body weight/h).…”

“…Little is known about the role of CRYAB in the CNS. Recent studies have revealed a protective role for CRYAB in a mouse model of multiple sclerosis [experimental autoimmune encephalomyelitis (EAE)], stroke (Arac et al, 2011), and Alexander disease (Ousman et al, 2007;Hagemann et al, 2009). In EAE, CRYAB acts as a negative modulator of inflam-mation and prevents demyelination and disease symptoms (Ousman et al, 2007).…”

Antiapoptotic Properties of α-Crystallin–Derived Peptide Chaperones and Characterization of Their Uptake Transporters in Human RPE Cells

“…Thus, it is likely that extracellular action of aB-crystallin may contribute to its recently reported anti-inflammatory effects in in vivo model systems. 36,37 On the other hand, the aB-crystallin mini-chaperone is taken up by hfRPE by specific transporters so that the mini-chaperone may act both intracellularly and extracellularly. Nanoparticles containing aB-crystallin minichaperone showed a prominent and uniform uptake by hfRPE cells.…”