Endogenous ghrelin's role in hippocampal neuroprotection after global cerebral ischemia: does endogenous ghrelin protect against global stroke?

Abstract

Ghrelin is a gastrointestinal hormone with a well-characterized role in feeding and metabolism. Recent evidence suggests that ghrelin may also be neuroprotective after injury in animal models of cerebral ischemia. Thus exogenous ghrelin treatment can improve cell survival, reduce infarct size, and rescue memory deficits in focal ischemia models, doing so by suppressing inflammation and apoptosis. Endogenous ghrelin plays a key a role in a number of physiological processes, including feeding, metabolism, stress, and anxiety. However, no study has examined whether endogenous ghrelin also contributes to neuroprotection after cerebral ischemia. Here, we aimed to determine whether endogenous ghrelin normally protects against neuronal cell death and cognitive impairments after global cerebral ischemia and whether such changes are linked with inflammation or apoptosis. We used a two-vessel occlusion (2VO) model of global cerebral ischemia in wild-type (wt) and ghrelin knockout (ghr-/-) C57/Bl6J mice. ghr-/- mice had improved cell survival in the Cornu Ammonis(CA)-2/3 region of the hippocampus-a region of significant growth hormone secretagogue receptor expression. They also displayed less cellular degeneration than wt mice after the 2VO (Fluoro-Jade) and had less cognitive impairment in the novel object-recognition test. These outcomes were despite evidence of more neuroinflammation and apoptosis in the ghr-/- and less of a postsurgery hypothermia. Finally, we found that mortality in the week following the 2VO was reduced more in ghr-/- mice than in wt. Overall, these experiments point to a neurodegenerative but antiapoptotic effect of endogenous ghrelin in this model of global ischemia, highlighting that further research is essential before we can apply ghrelin treatments to neurodegenerative insults in the clinic.

Ghrelin Plasma Levels After 1 Year of Ketogenic Diet in Children With Refractory Epilepsy

“…The ghrelin analog JMV-1843 rescued neurons and astrocytes in the pilocarpine model of status epilepticus (26). Beneficial effects were also reported for ghrelin in models of cerebral ischemia, although they have still to be clearly defined (27, 28). Interestingly, low ghrelin levels have been related to enhanced risk of liver damage in children undergoing surgery (29).…”

Dopamine neuronal protection in the mouse Substantia nigra by GHSR is independent of electric activity

“…Peripheral administration of GHSR agonists have been shown to inhibit oxidative stress, apoptosis, proinflammatory cytokine production, microglia activation, mitochondrial dysfunction, and excitotoxicity both in vivo and in vitro [16], [67], [68], [69], [70], [71], as well as exert neuroprotective effects against hippocampal and cortical neuronal death [68], [72], [73], [74]. Through these actions, GHSR has thus been linked to neuroprotection in several CNS diseases such as stroke [75], Alzheimer disease [72], [76], Parkinson disease [11], [12], [13], [69], [77], multiple sclerosis [78], [79], epilepsy [80], [81], and spinal cord injury [82]. Nevertheless, GHSRs have been shown to display higher constitutive basal activity in the absence of ligand [83], suggesting that (1) GHSR-mediated pathways do not need acyl ghrelin gene products to be activated but are modulated by them; (2) the existence of other(s) endogenous ligand(s) able to regulate GHSR activity in the midbrain and other brain areas.…”

Ghrelin gene products, receptors, and GOAT enzyme: biological and pathophysiological insight

“…It has been shown that UAG can induce proliferation of neuronal precursor cells in the rat fetal spinal cord (Sato et al 2006); however, the role of obestatin and ghrelin splice variants remains unexplored. Kenny et al 2013). Of note, the actions of ghrelin in neuroprotection seem to be specifically mediated by the inhibition of proapoptotic molecules associated with mitochondrial pathways and by activating endogenous protective molecules (Miao et al 2007).…”