cog1410 and Disease-Models--Animal

Traumatic brain injury (TBI) disrupts the blood-brain barrier (BBB) and reduces cerebral glucose uptake. Vascular endothelial growth factor (VEGF) is believed to play a key role in TBI, and COG1410 has demonstrated neuroprotective activity in several models of TBI. However, the effects of COG1410 on VEGF and glucose metabolism following TBI are unknown. The current study aimed to investigate the expression of VEGF and glucose metabolism effects in C57BL/6J male mice subjected to experimental TBI. The results showed that controlled cortical impact (CCI)-induced vestibulomotor deficits were accompanied by increases in brain edema and the expression of VEGF, with a decrease in cerebral glucose uptake. COG1410 treatment significantly improved vestibulomotor deficits and glucose uptake and produced decreases in VEGF in the pericontusion and ipsilateral hemisphere of injury, as well as in brain edema and neuronal degeneration compared with the control group. These data support that COG1410 may have potential as an effective drug therapy for TBI.

Topics: Animals; Apolipoproteins E; Blood-Brain Barrier; Brain Edema; Brain Injuries, Traumatic; Disease Models, Animal; Fluorodeoxyglucose F18; Glucose; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Positron Emission Tomography Computed Tomography; Vascular Endothelial Growth Factor A

Tristetraprolin (TTP), a negative regulator of many pro-inflammatory genes, is strongly expressed in rheumatoid synovial cells. The mitogen-activated protein kinase (MAPK) p38 pathway mediates the inactivation of TTP via phosphorylation of two serine residues. We wished to test the hypothesis that these phosphorylations contribute to the development of inflammatory arthritis, and that, conversely, joint inflammation may be inhibited by promoting the dephosphorylation and activation of TTP.. The expression of TTP and its relationship with MAPK p38 activity were examined in non-inflamed and rheumatoid arthritis (RA) synovial tissue. Experimental arthritis was induced in a genetically modified mouse strain, in which endogenous TTP cannot be phosphorylated and inactivated. In vitro and in vivo experiments were performed to test anti-inflammatory effects of compounds that activate the protein phosphatase 2A (PP2A) and promote dephosphorylation of TTP.. TTP expression was significantly higher in RA than non-inflamed synovium, detected in macrophages, vascular endothelial cells and some fibroblasts and co-localised with MAPK p38 activation. Substitution of TTP phosphorylation sites conferred dramatic protection against inflammatory arthritis in mice. Two distinct PP2A agonists also reduced inflammation and prevented bone erosion. In vitro anti-inflammatory effects of PP2A agonism were mediated by TTP activation.. The phosphorylation state of TTP is a critical determinant of inflammatory responses, and a tractable target for novel anti-inflammatory treatments.

Topics: Amino Alcohols; Animals; Apolipoproteins E; Arthritis, Rheumatoid; Cytokines; Disease Models, Animal; Endothelial Cells; Enzyme Activation; Fibroblasts; Humans; Macrophages; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Molecular Targeted Therapy; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein Phosphatase 2; RNA, Messenger; Serine; Synovial Membrane; Tristetraprolin

The degree of post-traumatic brain edema and dysfunction of the blood-brain barrier (BBB) influences the neurofunctional outcome after a traumatic brain injury (TBI). Previous studies have demonstrated that the administration of apolipoprotein E-mimetic peptide COG1410 reduces the brain water content after subarachnoid hemorrhage, intra-cerebral hemorrhage, and focal brain ischemia. However, the effects of COG1410 on vasogenic edema following TBI are not known. The current study evaluated the effects of 1 mg/kg daily COG1410 versus saline administered intravenously after a controlled cortical impact (CCI) injury on BBB dysfunction and vasogenic edema at an acute stage in mice. The results demonstrated that treatment with COG1410 suppressed the activity of matrix metalloproteinase-9, reduced the disruption of the BBB and Evans Blue dye extravasation, reduced the TBI lesion volume and vasogenic edema, and decreased the functional deficits compared with mice treated with vehicle, at an acute stage after CCI. These findings suggest that COG1410 is a promising preclinical therapeutic agent for the treatment of traumatic brain injury.

Topics: Animals; Apolipoproteins E; Behavior, Animal; Blood-Brain Barrier; Brain Edema; Brain Injuries; Disease Models, Animal; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Recovery of Function

This study investigated the neuroprotective effects of COG1410, an apoliporotein E (apoE)-derived mimic peptide, against early brain injury (EBI) after subarachnoid hemorrhage (SAH). SAH was induced in C57BL/6J mice (n=68) by endovascular perforation. Mice received intravenous injection of COG1410 (2mg/kg) or equal volume of vehicle (saline). The mortality rate, neurological score, rotarod latencies, cell apoptosis, microglial activation, pro-inflammatory cytokines production and protein levels of apoptotic and inflammatory markers were assessed at 24h after sham operation or SAH. Results showed that COG1410 alleviated the neurological deficits associated with SAH. Compared with vehicle treatment group, the number of apoptotic cells and activated microglia decreased significantly in the COG1410 treated group. COG1410 enhanced Akt activation and suppressed caspase-3 cleavage. The imbalance of Bax and Bcl-2 induced by SAH was regulated by COG1410. Additionally, COG1410 attenuated cytokines production of IL-1β, IL-6 and TNF-α and suppressed the activation of JNK/c-Jun and NF-κB. Taken together, COG1410 protected against EBI via reducing apoptosis and neuroinflammation, through mechanisms that involve the regulation of apoptotic signaling and microglial activation. COG1410 is a potential neuroprotective agent for SAH treatment.

Topics: Animals; Apolipoproteins E; Apoptosis; Cerebral Cortex; Disease Models, Animal; Encephalitis; Interleukin-1beta; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; Subarachnoid Hemorrhage; Survival Analysis; Tumor Necrosis Factor-alpha

Apolipoprotein E (apoE), a plasma protein responsible for transporting lipid and cholesterol, modulates responses of the central nervous system to injury. Small peptides derived from the receptor-binding region of apoE can simulate some important bioactivities of apoE holoprotein and offer neuroprotection against brain injury. We tested whether COG1410, an apoE-mimetic peptide, provides protection in a rat model of spinal cord injury (SCI). Traumatic injury was created at T8 by a cortical impact device. Injured rats were randomized to four treatment groups: vehicle, 0.15, 0.3, or 0.6 mg/kg COG1410; sham surgery rats received vehicle. Basso, Beattie, Bresnahan neurological score was evaluated prior to injury and at 1, 3, 7, and 14 days after injury. Histological changes were evaluated at 14 days. All injured rats lost body weight during the first week following injury. Body weight recovery was significantly improved in rats treated with COG1410. Mechanical impact resulted in severe motor deficit, and most animals had a BBB score of 0-1 at 24 hours postinjury. COG1410-treated rats showed significantly improved functional recovery and ameliorated motor deficit at 14 days postinjury. Histological analysis showed that COG1410 groups had a significantly reduced lesion size at the site of injury, a larger preserved luxol fast blue-stained area, and more visible neurons in the surrounding area of injury. Microglial activation was also significantly suppressed. These findings indicate that this apoE mimetic effectively improved neurological and histological outcome following SCI in rats, and the effect was associated with inhibition of microglial activation.

Topics: Animals; Apolipoproteins E; Body Weight; Cell Death; Disease Models, Animal; Dose-Response Relationship, Drug; Leukoencephalopathies; Male; Microglia; Movement Disorders; Neurologic Examination; Neurons; Rats; Rats, Wistar; Recovery of Function; Spinal Cord Injuries

Growing clinical evidence implicates isoform-specific effects of apolipoprotein E (apoE) in reducing neuroinflammation and mediating adaptive responses following ischemic and traumatic brain injury. However, the intact apoE holoprotein does not cross the blood-brain barrier and thus has limited therapeutic potential. We have created a small peptide, COG1410 (acetyl-AS-Aib-LRKL-Aib-KRLL-amide), derived from the apoE receptor-binding region. COG1410 retains the anti-inflammatory and neuroprotective biological properties of the intact holoprotein and penetrates the blood-brain barrier. In the current study, we utilized a murine model of transient focal cerebral ischemia and reperfusion to demonstrate that intravenous (IV) administration of COG1410 reduces infarct volume and radiographic progression of infarct, and improves functional outcome as assessed by rotarod when delivered up to 4h after ischemia onset.

Topics: Analysis of Variance; Animals; Apolipoproteins E; Brain Edema; Brain Infarction; Chromatography, Liquid; Disease Models, Animal; Encephalitis; Functional Laterality; Gene Expression Regulation; Infarction, Middle Cerebral Artery; Magnetic Resonance Imaging; Male; Mass Spectrometry; Mice; Mice, Inbred C57BL; Movement Disorders; Recovery of Function; RNA, Messenger; Time Factors; Tumor Necrosis Factor-alpha

After age, the second largest risk factor for Alzheimer's disease (AD) is apolipoprotein E (APOE) genotype, where APOE4 is associated with lower apoE protein levels, more severer brain pathology, enhanced inflammation and disease. Small peptides corresponding to the receptor-binding region of apoE mimic the anti-inflammatory activity of the apoE holoprotein. These apoE mimetics greatly improve behavioral outcomes and neuronal survival in head trauma models that display AD pathology and neuronal loss.. To determine whether apoE mimetics change behavior, inflammation and pathology in CVND-AD (SwDI-APP/NOS2(-/-)) transgenic mice.. Starting at 9 months, apoE peptides were subcutaneously administered 3 times per week for 3 months followed by behavioral, histochemical and biochemical testing.. Treatment with apoE mimetics significantly improved behavior while decreasing the inflammatory cytokine IL-6, neurofibrillary tangle-like and amyloid plaque-like structures. Biochemical measures matched the visible pathological results.. Treatment with apoE mimetics significantly improved behavior, reduced inflammation and reduced pathology in CVND-AD mice. These improvements are associated with apoE-mimetic-mediated increases in protein phosphatase 2A activity. Testing in additional AD models showed similar benefits, reinforcing this novel mechanism of action of apoE mimetics. These data suggest that the combination of anti-inflammatory and neuroprotective activities of apoE mimetics represents a new generation of potential therapeutics for AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Apolipoproteins E; Behavioral Symptoms; Brain; Disease Models, Animal; Gene Expression Regulation; Humans; Interleukin-6; Maze Learning; Mice; Mice, Transgenic; Motor Activity; Mutation; Neurofibrillary Tangles; Nitric Oxide Synthase Type II; Phosphopyruvate Hydratase; RNA, Messenger; Time Factors; Transforming Growth Factor beta

Traumatic axonal injury (TAI) accounts for at least 35% of the morbidity and mortality in traumatic brain injury (TBI) patients without space-occupying lesions. It is also believed to be a key determinant of adverse outcomes such as cognitive dysfunction across the spectrum of TBI severity. Previous studies have shown that COG1410, a synthetic peptide derived from the apolipoprotein E (apoE) receptor binding region, has anti-inflammatory effects after experimental TBI, with improvements in cognitive recovery. However, the effects of COG1410 on axonal injury following TBI are not known. The current study evaluated the effects of 1 mg/kg daily COG1410 versus saline administered intravenously starting 30 min after controlled cortical impact (CCI) injury on pericontusional TAI in young, wild-type C57BL6/J male mice. We found that COG1410 did not affect the number of amyloid precursor protein (APP)-immunoreactive axonal varicosities in the pericontusional corpus callosum and external capsule at 24 h, but reduced APP-immunoreactive varicosities by 31% at 3 days (p=0.0023), and 36% at 7 days (p=0.0009). COG1410 significantly reduced the number of Iba1-positive cells with activated microglial morphology at all three time points by 21-30%. There was no effect of COG1410 on pericontusional white matter volume or silver staining at any time point. This indicates a possible effect of COG1410 on delayed but not immediate TAI. Future studies are needed to investigate the underlying mechanisms, therapeutic time window, and physiological implications of this effect.

Topics: Amyloid beta-Protein Precursor; Animals; Apolipoproteins E; Axons; Brain Injuries; Cerebral Cortex; Disease Models, Animal; Down-Regulation; Male; Mice; Mice, Inbred C57BL; Microglia; Neuroprotective Agents

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.

Topics: Animals; Apolipoproteins E; Brain Injuries; Cerebral Cortex; Cognition Disorders; Disease Models, Animal; Drug Administration Schedule; Hippocampus; Injections, Intraperitoneal; Injections, Intravenous; Male; Memory Disorders; Rats; Rats, Long-Evans; Recovery of Function

Apolipoprotein E (apoE) is the primary apolipoprotein synthesized in the brain in response to injury with known neuroprotective effects exerted through antioxidant, antiinflammatory, antiexcitotoxic, and neurotrophic mechanisms. We have previously demonstrated that COG1410, an apoE mimetic peptide, exerts neuroprotective and antiinflammatory effects in a murine model of traumatic brain injury (TBI). As in TBI, ischemia-reperfusion injury is a component of acute stroke, which displays a pharmacogenetic association with the APOE4 gene. Using an intraluminal middle cerebral occlusion (MCAO) model in rats, we found that a single intravenous injection of COG1410 at 120 min post-MCAO significantly improved vestibulomotor function, decreased poststroke locomotor asymmetry, and decreased infarct volume of the ipsilateral hemisphere. These results support further exploration of a novel apoE-mimetic peptide, COG1410, as a therapeutic treatment for stroke.

Topics: Animals; Apolipoproteins E; Brain; Disease Models, Animal; Infarction, Middle Cerebral Artery; Ketamine; Male; Motor Activity; Postural Balance; Rats; Rats, Sprague-Dawley

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).

Topics: Animals; Apolipoproteins E; Brain Injuries; Cerebral Cortex; Cognition Disorders; Coloring Agents; Disease Models, Animal; Fluoresceins; Injections, Intravenous; Male; Maze Learning; Nerve Degeneration; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Recovery of Function; Treatment Outcome

In this study, we assessed whether apolipoprotein E (APOE) polymorphism affects inflammatory responses and mortality in the caecal ligation and puncture model of peritonitis. In addition, we determined the effects of APOE mimetic peptide administration in this sepsis model. Differences in survival between targeted replacement mice expressing the human APOE3 allele (APOE3TR) and the APOE4 allele (APOE4TR) mice were assessed. In a separate series of experiments, COG1410, an apoE-mimetic peptide, was administered intravenously at 12-hour intervals for 72 hours and compared to vehicle-treated control animals. End-points included mortality and serum levels of interleukin-1beta, interleukin-6, interleukin-12 and tumour necrosis factor-alpha. Mice expressing the human APOE4 allele (n = 16) demonstrated an increase in mortality following caecal ligation and puncture compared with APOE3TR mice (n = 22; P = 0.039). Administration of the apolipoprotein E mimetic COG1410 was well tolerated and APOE3TR mice treated with peptide (n = 20) demonstrated a significant reduction in mortality compared with vehicle treated animals (n = 20; P = 0.007). A similar effect was also observed in APOE4TR animals, in which treatment with COG1410 was associated with reduced mortality compared with vehicle treatment (n =16 animals/group; P = 0.027). COG1410 was also associated with a reduction in TNFalpha, interleukin-1beta, interleukin-6 and interleukin-12 levels in both APOE3TR and APOE4TR (n = 5 animals/group) assessed at 24 hours. Thus, administration of an apolipoprotein E-mimetic peptide is well tolerated, suppresses inflammatory responses, and improves mortality in a caecal ligation and puncture model of sepsis.

Topics: Animals; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Disease Models, Animal; Genotype; Granulocyte-Macrophage Colony-Stimulating Factor; Interleukins; Ligation; Mice; Mice, Inbred C57BL; Polymorphism, Genetic; Sepsis; Survival Rate; Treatment Outcome; Tumor Necrosis Factor-alpha

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.

Topics: Animals; Anti-Inflammatory Agents; Apolipoproteins E; Brain; Brain Injuries; Cell Line; Disease Models, Animal; Encephalitis; Gliosis; Hippocampus; Injections, Intravenous; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; Peptides; Recovery of Function; Time Factors; Treatment Outcome

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.

Topics: Animals; Anti-Inflammatory Agents; Apolipoproteins E; Astrocytes; Brain Injuries; Disease Models, Animal; Dose-Response Relationship, Drug; Glial Fibrillary Acidic Protein; Gliosis; Male; Movement; Movement Disorders; Nerve Degeneration; Neuroprotective Agents; Peptides; Rats; Rats, Sprague-Dawley; Recovery of Function; Treatment Outcome