Neuroprotective pentapeptide CN-105 is associated with reduced sterile inflammation and improved functional outcomes in a traumatic brain injury murine model

Abstract

At present, there are no proven pharmacological treatments demonstrated to improve long term functional outcomes following traumatic brain injury(TBI). In the setting of non-penetrating TBI, sterile brain inflammatory responses are associated with the development of cerebral edema, intracranial hypertension, and secondary neuronal injury. There is increasing evidence that endogenous apolipoprotein E(apoE) modifies the neuroinflammatory response through its role in downregulating glial activation, however, the intact apoE holoprotein does not cross the blood-brain barrier due to its size. To address this limitation, we developed a small 5 amino acid apoE mimetic peptide(CN-105) that mimics the polar face of the apoE helical domain involved in receptor interactions. The goal of this study was to investigate the therapeutic potential of CN-105 in a murine model of closed head injury. Treatment with CN-105 was associated with a durable improvement in functional outcomes as assessed by Rotarod and Morris Water Maze and a reduction in positive Fluoro-Jade B stained injured neurons and microglial activation. Administration of CN-105 was also associated with reduction in mRNA expression of a subset of inflammatory and immune-related genes.

Apolipoprotein E as a novel therapeutic neuroprotection target after traumatic spinal cord injury

“…These studies indicate that exogenous apoE mimetic peptides can provide additional neuroprotection after SCI even after the expression of endogenous apoE is increased following injury. Neuroprotection of exogenous apoE mimetic peptides has also been demonstrated in several other neurological disease models, such as ischemia stroke (Tu et al, 2017; Wang et al, 2013), intracerebral hemorrhage (Lei et al, 2016; Laskowitz et al, 2012), traumatic brain injury (Laskowitz et al, 2017; Laskowitz et al, 2007), EAE, a model of human multiple sclerosis (Li et al, 2006), or the peripheral nerve injury (Li et al, 2010). These studies suggest that apoE mimetic peptides could be an important neuroprotective reagent after SCI and other neurological diseases.…”

“…To address this issue, a series of small apoE mimetic peptides derived from its receptor-binding region have been created (Laskowitz and Vitek, 2007; Laskowitz et al, 2006; Guptill et al, 2017). These peptides retain the anti-inflammatory and neuroprotective effects of the native apoE protein yet cross blood-brain-barrier (Lynch et al, 2003; Laskowitz et al, 2001; Laskowitz et al, 2007; Laskowitz et al, 2017). In the present study, we used apoE peptide, COG112, which is designed by fusion of apoE133–149 with a protein transduction domain antennapedia (Antp) to enhance blood-brain barrier (BBB) and cell membrane penetration.…”

“…In closed head injury paradigms, apoE −/− mice have decreased levels of antioxidant compounds (Lomnitski et al, 1999a; Lomnitski et al, 1997) and impaired functional recovery and neuronal loss (Chen et al, 1997a; Han and Chung, 2000). Notably, treatment with exogenous apoE decrease the anatomical and functional deficits in the animal models of several neurological diseases, such as ischemic stroke (Horsburgh et al, 2000; Tu et al, 2017), of Alzheimer's disease (Sarantseva et al, 2009), traumatic brain injury (Wang et al, 2007; Lynch et al, 2005; Laskowitz et al, 2010; Kaufman et al, 2010; Hoane et al, 2009; Laskowitz et al, 2017; Cao et al, 2016), or EAE (Li et al, 2006). These studies suggest that apoE plays important roles in neuroprotection after neurological diseases and injuries.…”

Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease

“…Using peptide mimetics that are structurally similar to the lipid binding class A amphipathic helix found in apoE, it is possible to regulate the lipidation and secretion of APOE. These peptides are so designed as to promote cholesterol trafficking, anti-inflammatory signaling and antithrombotic effectsproperties that have been used in targeting systemic disorders such as atherosclerosis and coronary artery disease [133] or acute brain injury models [134][135][136]. One example is an 18 amino acid peptide with no known natural homologs called 4F…”

“…Another APOE mimetic peptide derived from the receptor binding region of APOE α helix, CN-105 (Ac-V-S-R-R-R-NH2) has successfully completed Phase I clinical trial in patients with intracerebral hemorrhage (ICH) ( Table 1). This peptide is BBB penetrant and reduces neuroinflammation and neuronal injury in mouse models of acute brain injury mouse models [135,136] but this peptide has not been tested in rodent AD models. Given the beneficial role of APOE mimetics, future studies in AD mouse models and cell culture systems with such mimetics are warranted.…”