TABLE 1.
Preclinical evidence of compounds targeting brain energy metabolism.
| Treatment | Model | Results | References |
| Insulin signaling | |||
| Insulin | Human primary astrocytes | ↑ Glucose uptake and glycogen storage in astrocytes | Heni et al., 2011; Arnold et al., 2018 |
| Insulin (intranasal) | Aged APP/PS1/Tau (3Tg) AD mouse models | ↑ Cognition; ↓ Cerebral oxidative stress, tau phosphorylation, Aβ load | Barone et al., 2019 |
| GLP1-R agonists | |||
| Liraglutide | APP/PS1, 3Tg, Aβ1–42 ICV injections AD mouse model | ↑ Neuronal survival, synaptic function, learning and memory ↓ Neuroinflammation, amyloid plaque, hyperphosphorylated Tau | McClean et al., 2011, 2015; Hansen et al., 2016a,b; Qi et al., 2016; Chen et al., 2017 |
| Liraglutide | Aβ cortical injection in non-human primate | ↑ Insulin signaling, synapse number; ↓ Neuroinflammation | Lourenco et al., 2013; Batista et al., 2018 |
| Liraglutide | 5 × FAD AD mouse model | Restored defective metabolism of astrocytes (incl. lactate release); ↑ Neuroprotection through enhanced astrocytic glycolysis; ↑Cognition | Zheng et al., 2021 |
| Liraglutide | Rodent models of PD, stroke and TBI | ↑ Neuroprotection and behavioral activity in mouse and rat models of PD; ↑ Brain repair after cerebral ischemic injury; ↑ Cognition; ↓ neurodegeneration and neuroinflammation in mouse and rat models of TBI | Liu et al., 2015; Hansen et al., 2016b; Badawi et al., 2017; Bader et al., 2019; He et al., 2020 |
| Exendin-4 | 3Tg AD + STZ-induced-T2D mouse model | ↑ Plasma insulin levels; ↑ Aβ brain levels | Li et al., 2010 |
| Exendin-4 | Mouse and rat models of PD and TBI | ↑ Neuroprotection, adult neurogenesis, behavioral activity | Perry and Greig, 2005; Perry et al., 2007; Bertilsson et al., 2008; Harkavyi et al., 2008; Li et al., 2009; Eakin et al., 2013; Rachmany et al., 2013 |
| Metformin | |||
| Metformin | Primary rat astrocytes | ↑ Glycolysis and lactate production by astrocytes | Westhaus et al., 2017 |
| Metformin | High fat diet in mice and rats | ↑ Mitochondrial function, neuroprotection, cognition, autophagy in mouse models. One study showed no effect on cognition in rats (McNeilly et al., 2012) | McNeilly et al., 2012; Pintana et al., 2012; Lennox et al., 2014; Allard et al., 2016; Chen et al., 2021 |
| Ketogenic diet | |||
| KD | Rat | ↑ Brain GLUT1 and MCT1 levels | Leino et al., 2001 |
| KD | Mouse | ↑ Brain mitochondrial function, ATP levels, oxidative stress resistance | Sullivan et al., 2004 |
| KD, ketone ester | APP, APP/PS1, 3Tg AD mouse models | ↑ Glycolysis, mitochondrial functions, cognition, motor performance ↓ Anxiety, Aβ levels, hyperphosphorylated Tau | Van der Auwera et al., 2005; Beckett et al., 2013; Kashiwaya et al., 2013; Zhang et al., 2013; Pawlosky et al., 2017 |
| β-HB | MPTM-induced mouse model of PD | ↑ Mitochondrial function, motor performance | Tieu et al., 2003 |
| Caprylic triglyceride | SOD1-G93A mouse model of ALS | ↑ Neuroprotection, motor performance | Zhao et al., 2012 |
3Tg, triple transgenic; PS1, presenilin 1; Aβ, Amyloid β; AD, Alzheimer’s disease; ALS, Amyotrophic lateral sclerosis; APP, amyloid precursor protein; β-HB, β-hydroxybutyrate; GLUT1, glucose transporter 1; ICV, intracerebroventricular; GLP-1R, Glucagon-like peptide-1 receptor; KD, ketogenic diet; MCT1, monocarboxylate transporter 1; PD, Parkinson’s disease; STZ, Streptozotocin; T2D, Type 2 Diabetes.