scholarly journals Design and Synthesis of Brain Penetrant Glycopeptide Analogues of PACAP With Neuroprotective Potential for Traumatic Brain Injury and Parkinsonism

2022 ◽  
Vol 1 ◽  
Author(s):  
Christopher R. Apostol ◽  
Kelsey Bernard ◽  
Parthasaradhireddy Tanguturi ◽  
Gabriella Molnar ◽  
Mitchell J. Bartlett ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Animal Models ◽  
Pharmacokinetic Profile ◽  
Neuroprotective Effects ◽  
Drug Candidates ◽  
Design And Synthesis ◽  
Class B ◽  
Neuropeptide Hormone ◽  
The Central Nervous System

There is an unmet clinical need for curative therapies to treat neurodegenerative disorders. Most mainstay treatments currently on the market only alleviate specific symptoms and do not reverse disease progression. The Pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenous neuropeptide hormone, has been extensively studied as a potential regenerative therapeutic. PACAP is widely distributed in the central nervous system (CNS) and exerts its neuroprotective and neurotrophic effects via the related Class B GPCRs PAC1, VPAC1, and VPAC2, at which the hormone shows roughly equal activity. Vasoactive intestinal peptide (VIP) also activates these receptors, and this close analogue of PACAP has also shown to promote neuronal survival in various animal models of acute and progressive neurodegenerative diseases. However, PACAP’s poor pharmacokinetic profile (non-linear PK/PD), and more importantly its limited blood-brain barrier (BBB) permeability has hampered development of this peptide as a therapeutic. We have demonstrated that glycosylation of PACAP and related peptides promotes penetration of the BBB and improves PK properties while retaining efficacy and potency in the low nanomolar range at its target receptors. Furthermore, judicious structure-activity relationship (SAR) studies revealed key motifs that can be modulated to afford compounds with diverse selectivity profiles. Most importantly, we have demonstrated that select PACAP glycopeptide analogues (2LS80Mel and 2LS98Lac) exert potent neuroprotective effects and anti-inflammatory activity in animal models of traumatic brain injury and in a mild-toxin lesion model of Parkinson’s disease, highlighting glycosylation as a viable strategy for converting endogenous peptides into robust and efficacious drug candidates.

Parallel Human and Animal Models of Blast- and Concussion-Induced Tinnitus and Related Traumatic Brain Injury (TBI)

2013 ◽  
Author(s):  
Jinsheng Zhang ◽  
Anthony Cacace ◽  
E. M. Haacke ◽  
Bruce Berkowitz ◽  
Jiani Hu ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Animal Models

scholarly journals Unconventional animal models for traumatic brain injury and chronic traumatic encephalopathy

2021 ◽  
Author(s):  
Nicole L. Ackermans ◽  
Merina Varghese ◽  
Bridget Wicinski ◽  
Joshua Torres ◽  
Rita De Gasperi ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Animal Models ◽  
Chronic Traumatic Encephalopathy

scholarly journals Intraoperative hypothermia during vascular neurosurgical procedures

2009 ◽  
Vol 26 (5) ◽  
pp. E24 ◽  
Author(s):  
Raymond Choi ◽  
Robert H. Andres ◽  
Gary K. Steinberg ◽  
Raphael Guzman
Keyword(s):  
Traumatic Brain Injury ◽  
Clinical Trials ◽  
Brain Injury ◽  
Animal Models ◽  
Mild Hypothermia ◽  
Scientific Evidence ◽  
Neurosurgical Procedures ◽  
Ischemic Damage ◽  
Intraoperative Hypothermia ◽  
Improved Outcomes

Increasing evidence in animal models and clinical trials for stroke, hypoxic encephalopathy for children, and traumatic brain injury have shown that mild hypothermia may attenuate ischemic damage and improve neurological outcome. However, it is less clear if mild intraoperative hypothermia during vascular neurosurgical procedures results in improved outcomes for patients. This review examines the scientific evidence behind hypothermia as a treatment and discusses factors that may be important for the use of this adjuvant technique, including cooling temperature, duration of hypothermia, and rate of rewarming.

Predictors of Emotional Distress in Family Caregivers of Persons with Traumatic Brain Injury: A Systematic Review

2013 ◽  
Vol 14 (1) ◽  
pp. 113-129 ◽  
Author(s):  
Angelle M. Sander ◽  
Kacey Little Maestas ◽  
Allison N. Clark ◽  
Whitney N. Havins
Keyword(s):  
Systematic Review ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Family Caregivers ◽  
Emotional Distress ◽  
Future Research ◽  
Class Iii ◽  
Class B ◽  
Assessment And Treatment ◽  
Severe Tbi

The purpose of the current paper was to conduct a systematic review of the literature on predictors of emotional distress in caregivers of persons with traumatic brain injury (TBI), and to provide evidence-based classification for prognostic variables to guide future research and clinical practice. A search was conducted using PubMed, CINAHL and PsycINFO databases. The citations of resulting articles were also reviewed. Twenty-eight articles met inclusion criteria and were retained for review. Reviews were conducted in accordance with the 2011 edition of the American Academy of Neurology (AAN) Guidelines for classifying evidence for prognostic studies. Data abstraction revealed one Class I study, four Class II studies, eight Class III studies, and 15 Class IV studies. Results of the review indicated that caregivers’ report of neurobehavioural problems in the person with injury is a probable predictor of emotional distress for caregivers of persons with complicated mild, moderate or severe TBI (Class B evidence). The level of participation in the person with injury, level of support needed by the person with injury, and family systems functioning are probably predictors of emotional distress for caregivers of persons with severe TBI (Class B evidence). Executive functioning impairment in the person with injury, pre-injury emotional distress in caregivers, caregiver age, caregivers’ use of emotion-focused coping, and social support may possibly be risk factors for caregivers’ emotional distress (Class C evidence). Recommendations for future research and implications for assessment and treatment of family caregivers are discussed.

INTERLEUKIN-6 AFTER TRAUMATIC BRAIN INJURY: COMPARISON OF HUMANS AND TWO ANIMAL MODELS.

Shock ◽  
1996 ◽  
Vol 5 ◽  
pp. 19
Author(s):  
V. H.J. Hans ◽  
K. L. Kiening ◽  
T. Kossmann ◽  
M. C. Morganti-Kossmann ◽  
U. Thomale ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Animal Models ◽  
Interleukin 6

scholarly journals Large animal models of stroke and traumatic brain injury as translational tools

2018 ◽  
Vol 315 (2) ◽  
pp. R165-R190 ◽  
Author(s):  
Annabel J. Sorby-Adams ◽  
Robert Vink ◽  
Renée J. Turner
Keyword(s):  
Traumatic Brain Injury ◽  
Ischemic Stroke ◽  
Brain Injury ◽  
Animal Models ◽  
Animal Species ◽  
Experimental Models ◽  
Clinical Translation ◽  
Large Animal ◽  
Large Animal Models ◽  
Significant Burden

Acute central nervous system injury, encompassing traumatic brain injury (TBI) and stroke, accounts for a significant burden of morbidity and mortality worldwide. Studies in animal models have greatly enhanced our understanding of the complex pathophysiology that underlies TBI and stroke and enabled the preclinical screening of over 1,000 novel therapeutic agents. Despite this, the translation of novel therapeutics from experimental models to clinical therapies has been extremely poor. One potential explanation for this poor clinical translation is the choice of experimental model, given that the majority of preclinical TBI and ischemic stroke studies have been conducted in small animals, such as rodents, which have small lissencephalic brains. However, the use of large animal species such as nonhuman primates, sheep, and pigs, which have large gyrencephalic human-like brains, may provide an avenue to improve clinical translation due to similarities in neuroanatomical structure when compared with widely adopted rodent models. This purpose of this review is to provide an overview of large animal models of TBI and ischemic stroke, including the surgical considerations, key benefits, and limitations of each approach.

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