Table 2.
Therapeutic strategies evaluated in zebrafish models and their main effects, featuring different classes of molecules with neuroprotective and metabolic potential describing their mechanisms of action, observed effects, advantages, and limitation.
| Molecule (therapeutic group) | Mechanism of action | Observed effects | Advantages | Limitations | References |
|---|---|---|---|---|---|
| Protein-based drugs | |||||
| Liraglutide (GLP-1 agonist receptor) | Activation of GLP-1 receptors; modulation of neuronal excitability and inflammation; improvement of glucose metabolism | Promoted neuronal viability, reduced apoptosis, regulated neuroinflammatory responses, and exhibited anxiolytic and antidepressant-like effects | Clinically approved; demonstrated neuroprotective efficacy in multiple models; translational potential to humans | Requires parenteral administration; possible desensitization of GLP-1R with chronic use | Candeias et al. (2015), Abd el-Rady et al. (2021), Bertelli et al. (2021), and Urkon et al. (2025) |
| Tirzepatide (GIP and GLP-1 receptor agonist) | Dual activation of GIP and GLP-1 receptors; AMPK activation; antioxidant, anti-inflammatory, and anti-apoptotic actions | Improved cognitive performance, restored antioxidant and anti-inflammatory markers in DM2 zebrafish models | Enhanced efficacy via dual incretin signaling; broader metabolic and neuroprotective coverage | Limited long-term data on CNS effects; potential gastrointestinal adverse events | Hristov et al. (2025) and Misra et al. (2025) |
| BDNF (neurotrophin) | Activation of TrkB receptors; modulation of synaptic plasticity and neuronal survival | Enhanced learning, memory, and synaptic connectivity; conserved function between zebrafish and humans | High translational relevance; potent modulator of synaptic function. | Poor pharmacokinetic stability; limited ability to cross the BBB | Cohen-Cory et al. (2010), De Felice et al. (2014), Lucini et al. (2018), and Lucon-Xiccato et al. (2022) |
| PACAP38 (neuropeptide) | Modulation of cAMP/PKA pathways; antioxidant, anti-apoptotic, and anti-inflammatory effects | Protected neurons and sensory cells from oxidative stress; mitigated apoptosis in neurotoxic models | Broad neuroprotective spectrum; highly conserved peptide | Short half-life; poor stability; complex receptor signaling network | Kasica et al. (2016), Kasica-Jarosz et al. (2018), Ghanizada et al. (2019), and Cherait et al. (2025) |
| NGF (neurotrophin) | Activation of TrkA receptors; regulation of neuronal differentiation, repair, and maintenance | Promoted neuronal survival, cholinergic protection, and synaptic repair | Central for neuronal development; strong neuroregenerative properties | Limited BBB permeability; potential pro-nociceptive and inflammatory effects | Bathina and Das (2015), Xiao and Le (2016), and Gu et al. (2025) |
| Non-protein drugs | |||||
| Metformin (biguanide) | AMPK pathway activation; regulation of mitochondrial respiration and insulin sensitivity | Exhibited neuroprotective effects, reduced oxidative stress, improved mitochondrial function and neuronal survival | Safe, inexpensive, and well-characterized; multi-targeted cellular benefits | Limited brain penetration; variable efficacy in advanced neurodegenerative stages | Sportelli et al. (2020) and Reed et al. (2025) |
| Vildagliptin (DPP-4 inhibitor) | Inhibition of dipeptidyl peptidase-4 enzyme; prolongation of endogenous GLP-1 activity | Enhanced neuronal survival, reduced oxidative damage, and improved behavioral parameters in DM2 models | Oral drug with good safety profile; indirectly promotes neurotrophic effects | Moderate CNS activity; limited experimental evidence in zebrafish | Pariyar et al. (2022) |
| Sitagliptin (DPP-4 inhibitor) | Inhibition of DPP-4, increasing levels of active incretins and insulin sensitivity | Reduced brain inflammation and oxidative stress; improved cognition in Parkinson-like zebrafish. | Neuroprotective potential through indirect incretin pathway activation | Mechanistic specificity in CNS remains unclear; moderate efficacy | Mani and Arfeen (2024) |
| Pioglitazone (thiazolidinediones) | PPAR-γ activation; regulation of mitochondrial and insulin signaling pathways; reduction of neuroinflammation | Improved cognitive and behavioral outcomes; decreased inflammatory cytokines and oxidative damage. | Well-known anti-inflammatory profile; promising in metabolic and neurodegenerative contexts | Associated with weight gain and cardiovascular side effects | Hu et al. (2024) |
| Rosiglitazone (thiazolidinediones) | PPAR-γ agonist; promotes mitochondrial biogenesis and glucose utilization in neurons | Enhanced learning performance; mitigated oxidative stress and synaptic dysfunction in zebrafish CNS models | Restores mitochondrial activity and synaptic plasticity | Safety concerns regarding cardiac effects; limited CNS selectivity | Cai et al. (2025) |
These studies highlight the use of zebrafish as a translational model to investigate the relationship between metabolism, inflammation, and synaptic dysfunction.