COG1410, an apolipoprotein E-based peptide, improves cognitive performance and reduces cortical loss following moderate fluid percussion injury in the rat.

COG1410, a small, novel ApoE-mimetic peptide derived from the receptor binding region of apolipoprotein E (ApoE), has been classified as anti-inflammatory in nature and improves motor, sensorimotor, and cognitive dysfunction following cortical contusion injury (CCI). In order to further examine COG1410's preclinical efficacy on cognitive recovery, the present study evaluated COG1410 following moderate fluid percussion injury (FPI). Animals were prepared with a moderate, unilateral FPI over the hippocampus. Following FPI, animals received a regimen of five doses of COG1410 or vehicle at 2 and 4h (1.0mg/kg, i.v.) followed by additional doses administered 24, 48, and 72 h (1.0mg/kg, i.p.). Prior to injury, animals were trained for 4 days (4 trials/day) in the Morris water maze (MWM) and then tested for retrograde amnesia on post-FPI day 11 and then on a working memory task on day 18. Testing for motor dysfunction on the tapered balanced beam began on day 2 post-FPI. Administration of this regimen of COG1410 significantly improved retention of memory in the retrograde amnesia test compared to vehicle post-FPI. However, COG1410 did not significantly improve acquisition of working memory in the MWM. Motor dysfunction on the tapered beam post-FPI was improved in the COG1410-treated group compared to vehicle treatment. Cortical lesion analysis revealed that the COG1410-treated animals demonstrated significantly less tissue loss compared to vehicle-treated animals. The results of this study suggest that COG1410 significantly limited the behavioral dysfunction and tissue loss associated with FPI and demonstrated continued preclinical efficacy for TBI.

COG1410 improves cognitive performance and reduces cortical neuronal loss in the traumatically injured brain.

We have previously shown that a single dose of COG1410, a small molecule ApoE-mimetic peptide derived from the apolipoprotein E (ApoE) receptor binding region, improves sensorimotor and motor outcome following cortical contusion injury (CCI). The present study evaluated a regimen of COG1410 following frontal CCI in order to examine its preclinical efficacy on cognitive recovery. Animals were prepared with a bilateral CCI of the frontal cortex. A regimen of COG1410 (0.8mg/kg intravenously [IV]) was administered twice, at 30min and again at 24h post-CCI. Starting on day 11, the animals were tested for their acquisition of a reference memory task in the Morris water maze (MWM), followed by a working memory task in the MWM on day 15. Following CCI, the animals were also tested on the bilateral tactile adhesive removal test to measure sensorimotor dysfunction. On all of the behavioral tests the COG1410 group was no different from the uninjured sham group. Administration of the regimen of COG1410 significantly improved recovery on the reference and working memory tests, as well as on the sensorimotor test. Lesion analysis revealed that COG1410 significantly reduced the size of the injury cavity. Administration of COG1410 also reduced the number of degenerating neurons, as measured by Fluoro-Jade C staining, in the frontal cortex at 48h post-CCI. These results suggest that a regimen of COG1410 appeared to block the development of significant behavioral deficits and reduced tissue loss. These combined findings suggest that COG1410 appears to have strong preclinical efficacy when administered following traumatic brain injury (TBI).

COG1410, a novel apolipoprotein E-based peptide, improves functional recovery in a murine model of traumatic brain injury.

Traumatic brain injury (TBI) is a silent epidemic affecting approximately 1.4 million Americans annually, at an estimated annual cost of $60 billion in the United States alone. Despite an increased understanding of the pathophysiology of closed head injury, there remains no pharmacological intervention proven to improve functional outcomes in this setting. Currently, the existing standard of care for TBI consists primarily of supportive measures. Apolipoprotein E (apoE) is the primary apolipoprotein synthesized in the brain in response to injury, where it modulates several components of the neuroinflammatory cascade associated with TBI. We have previously demonstrated that COG133, an apoE mimetic peptide, improved functional outcomes and attenuated neuronal death when administered as a single intravenous injection at 30 min post-TBI in mice. Using the principles of rational drug design, we developed a more potent analog, COG1410, which expands the therapeutic window for the treatment of TBI by a factor of four, from 30 min to 2 h. Mice that received a single intravenous injection of COG1410 at 120 min post-TBI exhibited significant improvement on a short term test of vestibulomotor function and on a long term test of spatial learning and memory. This was associated with a significant attenuation of microglial activation and neuronal death in the hippocampus, the neuroanatomical substrate for learning and memory. Rationally derived apoE mimetic peptides have been demonstrated to exert neuroprotective and anti-inflammatory effects in vitro and in clinically relevant models of brain injury. This represents a novel therapeutic strategy in the treatment of TBI.

The novel apolipoprotein E-based peptide COG1410 improves sensorimotor performance and reduces injury magnitude following cortical contusion injury.

It has previously been shown that small peptide molecules derived from the apolipoprotein E (ApoE) receptor binding region are anti-inflammatory in nature and can improve outcome following head injury. The present study evaluated the preclinical efficacy of COG1410, a small molecule ApoE-mimetic peptide (1410 daltons), following cortical contusion injury (CCI). Animals were prepared with a unilateral CCI of the sensorimotor cortex (SMC) or sham procedure. Thirty mins post-CCI the animals received i.v. infusions of 0.8 mg/kg COG1410, 0.4 mg/kg COG1410, or vehicle. Starting on day 2, the animals were tested on a battery of behavioral measures to assess sensorimotor (vibrissae-forelimb placing and forelimb use-asymmetry), and motor (tapered balance beam) performance. Administration of the 0.8 mg/kg dose of COG1410 significantly improved recovery on the vibrissae-forelimb and limb asymmetry tests. However, no facilitation was observed on the tapered beam. The low dose (0.4 mg/kg) of COG1410 did not show any significant differences compared to vehicle. Lesion analysis revealed that the 0.8 mg/kg dose of COG1410 significantly reduced the size of the injury cavity compared to the 0.4 mg/kg dose and vehicle. The 0.8 mg/kg dose also reduced the number of glial fibrillary acid protein (GFAP+) reactive cells in the injured cortex. These results suggest that a single dose of COG1410 facilitates behavioral recovery and provides neuroprotection in a dose and task-dependent manner. Thus, the continued clinical development of ApoE based therapeutics is warranted and could represent a novel strategy for the treatment of traumatic brain injuries.

Apolipoprotein E-derived peptides ameliorate clinical disability and inflammatory infiltrates into the spinal cord in a murine model of multiple sclerosis.

Apolipoprotein E (apoE), well known to play a role in lipid transport and cholesterol metabolism, also exerts anti-inflammatory and neuroprotective effects in the central nervous system. Recent clinical and genetic studies display an association between apoE genotype (APOE) and the progression and severity of multiple sclerosis, raising the possibility that modulation of apoE may be a novel treatment for multiple sclerosis. Using a murine experimental autoimmune encephalomyelitis (EAE) model of human multiple sclerosis, we found that a peptidomimetic of apoE protein, COG133, substantially reduces the clinical symptoms of EAE and promotes remission from the disability when administered before or after onset of disease. Most notably, fusion of COG133 to a protein transduction domain creates COG112, a modified apoE-mimetic peptide with significantly enhanced anti-inflammatory bioactivities in vitro, and improved therapeutic effects on EAE in vivo, which renders a nearly full remission from the disability. Histopathological analysis showed that COG112 and COG133 attenuated demyelination and significantly diminished the number of peripheral cells infiltrating into the spinal cord. ApoE mimetics also interfered with several mechanisms relevant to the pathogenesis of EAE and multiple sclerosis, including activation of macrophages, subsequent production of nitric oxide and inflammatory cytokines, and lymphocyte proliferation. These data suggest that apoE mimetics represent a multidimensional therapeutic for multiple sclerosis capable of inhibiting the inflammatory cascade, modulating immune cell function, and reducing clinical signs, which may have novel utility for the treatment of inflammatory autoimmune diseases.