A Novel Cerebroprotein Hydrolysate, CH1, Ameliorates Chronic Focal Cerebral Ischemia Injury by Promoting White Matter Integrity via the Shh/Ptch-1/Gli-1 Signaling Pathway

Abstract

Purpose Strokes are devastating as there are no current therapies to prevent long-term neurological deficits. Previous studies reported that cerebroprotein hydrolysate (CH) plays a role in neuronal protection in acute phase after ischemic stroke, while the long-term effects of CH upon brain plasticity and neurological outcomes after stroke are still uncertain. To address these gaps, we assessed the effect of a new cerebroprotein hydrolysate, CH1, on long-term gray and white matter integrity as well as axonal plasticity in the late phase after ischemic stroke and the potential mechanisms. Methods Adult male mice were subjected to permanent distal middle cerebral artery occlusion (dMCAO), followed by daily intraperitoneal injection of CH1 for 14 days. Motor function was measured weekly through behavioral neurological evaluations. Gray matter intensity and white matter intensity were examined by immunofluorescence staining. The sonic hedgehog (Shh) inhibitor cyclopamine (CYC) was injected to determine the involvement of the Shh pathway in the therapeutic effects of CH1. Results We found that intraperitoneal delivery of CH1, compared to vehicle administration, significantly improved long-term neurological outcomes at various times and promoted neuronal viability at 14 days but not at 28 days after stroke. Importantly, CH1 mitigated stroke-induced white matter injury and facilitated axonal plasticity in the late stage after stroke. Conclusion These results unveil a previously unappreciated role for CH in the repair of white matter and brain plasticity after stroke.

The Cerebroprotein Hydrolysate-I Plays a Neuroprotective Effect on Cerebral Ischemic Stroke by Inhibiting MEK/ERK1/2 Signaling Pathway in Rats

“…7 The free amino acids of 50–80% can enter brain neurons through the blood brain barrier (BBB) and strengthen protein synthesis in the brain. 10 , 11 , 24 It can simulate similar pharmacodynamic characteristics of neurotrophic factors (NTFs), such as BDNF, NGF, and serum insulin-like growth factor-1 (IGF-1). 8 , 10 , 24 In the current experiment, it has been found that CH-I can promote the repair of neurons and subsequently improve the dementia symptoms and delay the aggravation of dementia lesions of vascular dementia (VaD) rats by elevating the level of IGF-1 in VaD rats.…”

“… 8 , 10 , 24 In the current experiment, it has been found that CH-I can promote the repair of neurons and subsequently improve the dementia symptoms and delay the aggravation of dementia lesions of vascular dementia (VaD) rats by elevating the level of IGF-1 in VaD rats. 14 Cao et al 11 have found that continuous intraperitoneal injection of CH-I 14d to MCAO mice can improve the mNSS score, promote neuronal survival, and significantly improve infarct size in mice. BDNF is among the most abundant NTFs in brain tissue, mainly expressed in the synapse of the hypothalamus, cortex, and the basal part of the forebrain.…”

“…Treated group and positive group: the CH-I and CBL were prepared into 1 mL solution with 0.9% normal saline, and the rats were intraperitoneally injected with CH-I (20 mg/kg) 11 and CBL (20 mg/kg) at 0, 3, 6, and 12 hours after reperfusion, respectively. The sham group and model group rats were given 1 mL normal saline simultaneously.…”

“… 8–11 It has been found that CH-I and cerebrolysin (CBL) have similar effects to brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), and have neuroprotective effects such as reducing the inflammatory response, apoptosis, and encephaledema. 8 , 9 , 11 BDNF is a protein synthesized in the brain, which is widespread in the central nervous system and can promote the recovery of function after stroke. 12 It has been noted that the expression of BDNF is decreased after stroke, and the neurobehavioral function of cerebral ischemia rats can be improved by up-regulating BDNF expression.…”

Cerebroprotein Hydrolysate-I Inhibits Hippocampal Neuronal Apoptosis by Activating PI3K/Akt Signaling Pathway in Vascular Dementia Mice

“…18 In a recent study, it was found that CH-I mitigated stroke-induced white matter injury and facilitated axonal plasticity in the late stage after stroke. 19 CBL can improve the cognitive ability and general function of VaD patients, 20 attenuate apoptosis of thalamic neurons 21 and improve the neurological function in middle cerebral artery occlusion (MCAO) rats. 22 Therefore, we speculate that CH-I and CBL may have similar neuroprotective effects.…”