Alpha Calcitonin Gene-Related Peptide Increases Cerebral Vessel Diameter in Animal Models of Subarachnoid Hemorrhage: A Systematic Review and Meta-analysis

Abstract

Delayed cerebral ischemia (DCI) is a life-threatening complication after subarachnoid hemorrhage. There is a strong association between cerebral vessel narrowing and DCI. Alpha calcitonin gene-related peptide (αCGRP) is a potent vasodilator, which may be effective at reducing cerebral vessel narrowing after subarachnoid hemorrhage (SAH). Here, we report a meta-analysis of data from nine in vivo animal studies identified in a systematic review in which αCGRP was administered in SAH models. Our primary outcome was change in cerebral vessel diameter and the secondary outcome was change in neurobehavioral scores. There was a 40.8 ± 8.2% increase in cerebral vessel diameter in those animals treated with αCGRP compared with controls (p < 0.0005, 95% CI 23.7–57.9). Neurobehavioral scores were reported in four publications and showed a standardized mean difference of 1.31 in favor of αCGRP (CI −0.49 to 3.12). We conclude that αCGRP reduces cerebral vessel narrowing seen after SAH in animal studies but note that there is insufficient evidence to determine its effect on functional outcomes.

Bilirubin Oxidation Products and Cerebral Vasoconstriction

“…While the least dilution (greatest concentration) of the BOXes mixture caused dilation and the greatest dilutions lacked both constrictor and dilator efficacy, intermediate dilutions caused constriction ( Clark et al, 2002 ; vehicle controls not reported). The constriction was relatively slow to develop, i.e., 40 min, and was still present at 24 h ( Clark et al, 2002 ), consistent with the prolonged vasospasm observed with SAH ( Crowley et al, 2008 ; Siasios et al, 2013 ; Flynn et al, 2017 ; Geraghty and Testai, 2017 ).…”

“…Additionally, the effect of BOXes was slow to reverse ( Hou et al, 2011 ). These findings of Hou et al (2011) are consistent with the ability of BOXes to traverse the membrane to act at a cytoplasmic site of Slo1 K + channels and, further, the sustained constriction following supradural application of BOXes ( Clark et al, 2002 ), the resistance to reversal of the constriction of cerebral vessels in brain slices (see below; Joerk et al, 2014 ), and the prolonged vasospasm following SAH ( Crowley et al, 2008 ; Siasios et al, 2013 ; Foreman, 2016 ; Flynn et al, 2017 ; Geraghty and Testai, 2017 ). In addition to a direct inhibitory effect of BOXes on Slo1 K + channels ( Hou et al, 2011 ), BOXes activation of protein kinase C ( Pyne-Geithman et al, 2008 ) may represent an additional signaling pathway for Slo1 K + channel inhibition.…”

“…To understand the relative roles of these multiple factors in SAH-induced pathobiology the involvement of these factors has been differentiated by the time courses for their appearances relative to the initiation of SAH: acute, early, and late ( Geraghty and Testai, 2017 ). Amongst the late developing contributory factors thought to negatively impact neurologic outcome is spasm of cerebral arteries ( Crowley et al, 2008 ; Siasios et al, 2013 ; Foreman, 2016 ; Flynn et al, 2017 ; Geraghty and Testai, 2017 ).…”

The Metabolic Rearrangements of Bariatric Surgery: Focus on Orexin-A and the Adiponectin System

“…Orexin-A exerts its functions by binding its receptors, Orexin-1 receptor (Ox1) and Orexin-2 receptor (Ox2), two G-protein coupled receptors [ 18 , 19 , 20 ]. The Orexin system is involved in physiological and pathophysiological processes [ 21 , 22 , 23 ] ( Figure 1 B). Many metabolic molecules influence Orexin-A activity; in particular, glucose, leptin, and amino acids and also some environmental factors increase Orexin-A levels during the waking phase of the circadian cycles and fasting or periods of caloric restriction.…”

Non-Rapid Eye Movement Sleep Parasomnias and Migraine: A Role of Orexinergic Projections

“…The relationship between sleep disturbance and migraine/headache could involve another fundamental neurobiological system, the orexin/hypocretin system, which seems to play a key role in regulating both the sleep/wake cycle and REM sleep ( 35 ), and it may also be associated with migraine pathogenesis. Indeed, orexin/hypocretin A and orexin/hypocretin B are hypothalamic excitatory neuropeptides that, in addition to regulating sleep/wake rhythm, play a role in many biological pathways involved in thermoregulation, energy metabolism control, mood and emotional regulation, energy homeostasis, reward mechanisms, drug dependence, cardiovascular responses, sexual behavior, nutritional behavior, and spontaneous physical activity ( 36 – 38 ). It is interesting to note that some symptoms associated with migraine such as tiredness, yawning, drowsiness, and desire for certain foods may be due to an involvement of the orexin/hypocretin system.…”