Ghrelin Shows Promise Against Alzheimer's and Parkinson's in Animal Studies

Ghrelin, a 28-amino-acid orexigenic peptide secreted primarily by the stomach, has long been known as the 'hunger hormone' for its roles in appetite stimulation, growth hormone release, and energy homeostasis. Over the past decade, however, mounting preclinical evidence has pointed to potent neuroregenerative and neuroprotective properties mediated via the growth hormone secretagogue receptor 1a (GHS-R1a), which is expressed in the hippocampus and hypothalamus. This systematic review is the first to comprehensively synthesize that evidence across both Alzheimer's disease (AD) and Parkinson's disease (PD), two of the most prevalent and burdensome neurodegenerative conditions worldwide, affecting roughly 50 million and 1 million people respectively in the UK and US combined.

Following PRISMA guidelines, researchers searched Embase, Cochrane, and Medline from January 2010 to July 2023 without language restriction, yielding 648 initial records. After duplicate removal, title/abstract screening, and full-text evaluation, 14 animal studies were included — 8 focused on AD and 6 on PD. All were rodent experiments (mice or rats, including wild-type, transgenic, and specific disease-model strains). Sample sizes ranged from 18 to 60 animals per study, with most between 18 and 36. Disease pathology was induced either via stereotactic injection of neurotoxins (e.g., Aβ 1-42, 6-OHDA, MPTP) or by using established transgenic models. Risk of bias was assessed using the SYRCLE tool; most domains were rated 'unclear' due to insufficient reporting of randomization and blinding procedures.

For AD, the eight included studies consistently showed that AG administration — delivered peripherally or centrally — reduced amyloid-beta (Aβ) plaque burden, decreased hyperphosphorylated tau and neurofibrillary tangles, improved hippocampal synaptic plasticity, and enhanced performance on spatial memory tasks such as the Morris Water Maze. Several studies reported statistically significant reductions in Aβ deposition and improvements in cognitive scores (p < 0.05 in all reporting studies). One study noted that AG significantly upregulated brain-derived neurotrophic factor (BDNF) expression in the hippocampus, a key mediator of neurogenesis. Importantly, the unacylated form (UAG) showed no binding affinity for GHS-R1a in brain tissue and produced no comparable neuroprotective effects in these models.

For PD, the six included studies demonstrated that AG preserved tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra and attenuated striatal dopamine depletion induced by 6-OHDA or MPTP. Neuroprotective effects were most pronounced when ghrelin was administered early in the disease course, before significant neuronal loss had occurred. Motor function assessments — including rotarod performance and pole tests — showed meaningful improvements in ghrelin-treated animals versus vehicle controls (p < 0.05 across reporting studies). One South Korean study found that GHS-R1a agonist treatment at early PD stages rescued roughly 30–40% of dopaminergic neurons that would otherwise have been lost.

A critical pharmacological limitation is ghrelin's rapid in vivo degradation: more than half of administered AG is des-octanoylated within 6 hours in human serum, at a rate of 0.019 ± 0.001 μmol·min⁻¹·mL⁻¹, by enzymes including butyrylcholinesterase and carboxylesterase. Additionally, proteolysis occurs at five identified cleavage sites in stomach, liver, and kidney homogenates within just 2 hours. This short half-life poses a major challenge for translating animal findings to human use. The authors argue that developing metabolically stable GHS-R1a agonists or optimized delivery systems (e.g., nanoparticles, sustained-release formulations) is the critical next step. The complete absence of human clinical trials represents the most significant gap in the evidence base, and the authors explicitly call for well-designed Phase I/II trials before any clinical recommendations can be made.