Targeting Metabolic Pathways for Neurodegeneration: The Emerging Role of Anti-Diabetic and Lipid-Lowering Agents

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Vol. 13 No. 4 (2025): 2025 Volume -13 - Issue 4

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November 7, 2025
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Targeting Metabolic Pathways for Neurodegeneration: The Emerging Role of Anti-Diabetic and Lipid-Lowering Agents

https://doi.org/10.61096/ijamscr.v13.iss4.2025.633-642
Vaishnaav M
Master of Pharmacy, Department of Pharmaceutics, J.S.S. College of Pharmacy, Bangalore–Mysore Road, Narasimha Raj Mohalla, Bannimantap A Layout, Bannimantap, Mysuru, Karnataka – 570015, India
Nandhini K
Master of Pharmacy, Department of Pharmaceutics, J.S.S. College of Pharmacy, Bangalore–Mysore Road, Narasimha Raj Mohalla, Bannimantap A Layout, Bannimantap, Mysuru, Karnataka – 570015, India
Aathmika A
Master of Pharmacy, Department of Pharmaceutical chemistry, J.S.S. College of Pharmacy, Bangalore–Mysore Road, Narasimha Raj Mohalla, Bannimantap A Layout, Bannimantap, Mysuru, Karnataka – 570015, India
Srikanth Malavalli Siddalingegowda
Master of Pharmacy, Department of Pharmacy Practice,J.S.S. College of Pharmacy, Bangalore–Mysore Road, Narasimha Raj Mohalla, Bannimantap A Layout, Bannimantap, Mysuru, Karnataka – 570015, India

Corresponding Author(s) : Srikanth Malavalli Siddalingegowda

srikanthmalavalli@gmail.com

International Journal of Allied Medical Sciences and Clinical Research, Vol. 13 No. 4 (2025): 2025 Volume -13 - Issue 4

Abstract

Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD) represent a significant and growing global health burden. Despite extensive research, effective disease-modifying therapies remain elusive. Recent insights into the shared pathophysiological pathways between metabolic syndromes and neurodegeneration particularly mitochondrial dysfunction, insulin resistance, oxidative stress, and chronic inflammation have opened new therapeutic opportunities. The concept of drug repurposing, wherein existing anti-metabolic drugs like anti-diabetics and lipid-lowering agents are evaluated for neuroprotective efficacy, offers a promising translational route to accelerate therapeutic discovery. Agents such as metformin, pioglitazone, GLP-1 receptor agonists, and statins have demonstrated neurorestorative and anti-inflammatory effects in preclinical and early clinical settings. Moreover, AMP-activated protein kinase (AMPK) activation, peroxisome proliferator-activated receptor gamma (PPARγ) modulation, and enhancement of insulin signaling appear central to their neuroprotective mechanisms. This review consolidates mechanistic evidence, preclinical data, and emerging clinical trials supporting the repositioning of anti-metabolic agents for neurodegenerative disease modification, with a focus on molecular pathways, pharmacodynamic interactions, and translational challenges. It also highlights future perspectives, emphasizing combinatorial and precision medicine strategies integrating metabolomics, neuroimaging, and artificial intelligence to optimize therapeutic repurposing for neurodegenerative diseases.

Keywords

Drug repurposing, neurodegenerative diseases, anti-diabetic drugs, lipid-lowering agents, insulin resistance, mitochondrial dysfunction
1.
M V, K N, A A, Siddalingegowda SM. Targeting Metabolic Pathways for Neurodegeneration: The Emerging Role of Anti-Diabetic and Lipid-Lowering Agents. Int. J. of Allied Med. Sci. and Clin. Res. [Internet]. 2025 Nov. 7 [cited 2025 Dec. 8];13(4):633-42. Available from: https://ijamscr.com/ijamscr/article/view/1681
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References
  1. Wyss-Coray T, Rogers J. Inflammation in Alzheimer disease a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med. 2012;2(1):a006346.
  2. De la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetes–evidence reviewed. J Diabetes Sci Technol. 2008;2(6):1101–13.
  3. Arnold SE, Arvanitakis Z, Macauley-Rambach SL, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol. 2018;14(3):168–81.
  4. Pushpakom S, Iorio F, Eyers PA, et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019;18(1):41–58.
  5. Cavalli A, Bolognesi ML, Minarini A, et al. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem. 2008;51(3):347–72.
  6. Cheng CM, Reinhardt RR, Lee WH, et al. Insulin-like growth factor 1 regulates developing brain glucose metabolism. Proc Natl Acad Sci U S A. 2000;97(18):10236–41.
  7. Corsello SM, Bittker JA, Liu Z, et al. The Drug Repurposing Hub: a next-generation drug library and information resource. Nat Med. 2017;23(4):405–8.
  8. Imfeld P, Bodmer M, Jick SS, Meier CR. Metformin, other antidiabetic drugs, and risk of Alzheimer’s disease: a population-based case-control study. J Am Geriatr Soc. 2012;60(5):916–21.
  9. Haag MD, Hofman A, Koudstaal PJ, Stricker BH, Breteler MM. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity: the Rotterdam Study. J Neurol Neurosurg Psychiatry. 2009;80(1):13–7.
  10. Mattson MP, Arumugam TV. Hallmarks of brain aging: adaptive and pathological modification by metabolic states. Cell Metab. 2018;27(6):1176–99.
  11. Craft S. Insulin resistance and Alzheimer’s disease pathogenesis: potential mechanisms and implications for treatment. Curr Alzheimer Res. 2007;4(2):147–52.
  12. Bose A, Beal MF. Mitochondrial dysfunction in Parkinson's disease. J Neurochem. 2016;139(S1):216–31.
  13. Heneka MT, Golenbock DT, Latz E. Innate immunity in Alzheimer's disease. Nat Immunol. 2015;16(3):229–36.
  14. Puglielli L, Tanzi RE, Kovacs DM. Alzheimer’s disease: the cholesterol connection. Nat Neurosci. 2003;6(4):345–51.
  15. Viollet B, Guigas B, Garcia NS, et al. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122(6):253–70.
  16. Kickstein E, Krauss S, Thornhill P, et al. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc Natl Acad Sci U S A. 2010;107(50):21830–5.
  17. Heneka MT, Landreth GE. PPARs in the brain. Biochim Biophys Acta. 2007;1771(8):1031–45.
  18. Gold M, Alderton C, Zvartau-Hind M, et al. Rosiglitazone monotherapy in mild-to-moderate Alzheimer’s disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord. 2010;30(2):131–46.
  19. Holscher C. Potential role of glucagon-like peptide-1 (GLP-1) in neuroprotection. CNS Drugs. 2012;26(10):871–82.
  20. Gejl M, Brock B, Egefjord L, et al. Blood-brain glucose transfer in Alzheimer’s disease: effect of GLP-1 analog treatment. Sci Rep. 2017;7(1):17490.
  21. Wood WG, Eckert GP, Igbavboa U, Müller WE. Statins and neuroprotection: a prescription to move the field forward. Ann N Y Acad Sci. 2010;1199:69–76.
  22. Jiang P, Mukthavaram R, Chao Y, et al. Inhibition of mevalonate pathway by simvastatin induces autophagy in glioblastoma cells. Mol Cancer Ther. 2014;13(2):394–404.
  23. Sparks DL, Sabbagh MN, Connor DJ, et al. Atorvastatin for the treatment of mild to moderate Alzheimer disease. Arch Neurol. 2005;62(5):753–7.
  24. McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia. Cochrane Database Syst Rev. 2016;1:CD003160.
  25. Lin FC, Tsai PH, Lee YC, et al. Lipophilic statins and the risk of dementia: a nationwide population-based study. Eur J Neurol. 2018;25(7):1042–9.
  26. Zolezzi JM, Santos MJ. PPARs in the central nervous system: roles in neurodegeneration and neuroinflammation. Biol Rev Camb Philos Soc. 2020;95(2):668–88.
  27. Carta AR, Pisanu A. Modulation of microglia activity by PPAR-γ agonists: is neuroinflammation relevant for Parkinson's disease? Parkinsons Dis. 2013;2013:1–11.
  28. Seidah NG, Awan Z, Chretien M, Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ Res. 2014;114(6):1022–36.
  29. Sun X, Essalmani R, Day R, Khatib AM, Seidah NG. The proprotein convertase PCSK9 is required for the differentiation of cortical neurons. J Biol Chem. 2011;286(48):43126–34.
  30. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13(4):251–62.
  31. Ma T, Chen Y, Vingtdeux V, et al. Inhibition of AMPK suppresses Aβ generation by modulating APP processing and degradation. J Neurosci. 2014;34(3):911–27.
  32. Canto C, Auwerx J. Targeting sirtuin 1 to improve metabolism: all you need is NAD+? Pharmacol Rev. 2012;64(1):166–87.
  33. Moreno S, Farioli-Vecchioli S, Cerù MP. Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS. Neuroscience. 2004;123(1):131–45.
  34. Patil SP, Jain PD, Ghumatkar PJ, Tambe R, Sathaye S. Neuroprotective effect of metformin in MPTP-induced Parkinson's disease in mice. Neuroscience. 2014;277:747–54.
  35. Breidert T, Callebert J, Heneka MT, et al. Protective action of the peroxisome proliferator–activated receptor-γ agonist pioglitazone in a mouse model of Parkinson's disease. J Neurochem. 2002;82(3):615–24.
  36. Ou Z, Kong X, Sun X, He X, Zhang L, Gong Z. Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. Brain Behav Immun. 2018;69:351–63.
  37. McClean PL, Gault VA, Harriott P, Hölscher C. Glucagon-like peptide-1 analogues enhance synaptic plasticity in the brain: a link between diabetes and Alzheimer's disease. Eur J Pharmacol. 2010;630(1–3):158–62.
  38. Athauda D, Foltynie T. Insulin resistance and Parkinson’s disease: a new target for disease modification? Prog Neurobiol. 2016;145–146:98–120.
  39. Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10103):1664–75.
  40. Gejl M, Gjedde A, Egefjord L, et al. In Alzheimer’s disease, 6-month treatment with GLP-1 analog prevents decline of brain glucose metabolism: randomized, placebo-controlled, double-blind clinical trial. Front Aging Neurosci. 2016;8:108.
  41. Campbell JM, Stephenson MD, de Courten B, Chapman I, Bellman SM, Aromataris E. Metformin use associated with reduced risk of dementia in patients with diabetes: a systematic review and meta-analysis. J Alzheimers Dis. 2018;65(4):1225–36.
  42. Sano M, Bell KL, Galasko D, et al. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer’s disease. Neurology. 2011;77(6):556–63.
  43. Poly TN, Islam MM, Yang HC, Wu CC, Li YJ. Association between statin use and risk of dementia: a meta-analysis of observational studies. Neuroepidemiology. 2020;54(3):214–23.
  44. Tufekci KU, Genc S, Genc K. The endotoxin-induced neuroinflammation model of Parkinson's disease. Parkinsons Dis. 2011;2011:487450.
  45. Salcedo I, Tweedie D, Li Y, Greig NH. Neuroprotective and neurotrophic actions of glucagon-like peptide-1: an emerging opportunity to treat neurodegenerative and cerebrovascular disorders. Br J Pharmacol. 2012;166(5):1586–99.
  46. Shukla A, Agarwal P, Vishwakarma S, et al. Synergistic neuroprotective effects of pioglitazone and atorvastatin against ischemic stroke. Mol Neurobiol. 2018;55(8):6636–48.
  47. Challa TD, Wueest S, Lucchini FC, et al. Combined PPARα/γ agonism improves insulin sensitivity and reduces atherosclerosis in ApoE-deficient mice. Diabetologia. 2019;62(11):1988–2000.
  48. Mattson MP, Moehl K, Ghena N, Schmaedick M, Cheng A. Intermittent metabolic switching, neuroplasticity, and brain health. Nat Rev Neurosci. 2018;19(2):81–94.
  49. Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx. 2005;2(1):3–14.
  50. Garcia D, Shaw RJ. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell. 2017;66(6):789–800.
  51. Mullins R, Reiter D, Kapogiannis D. Metabolic dysfunction in Alzheimer's disease: therapeutic approaches targeting glucose and lipid metabolism. Cell Mol Life Sci. 2018;75(20):3967–83.
  52. Nosengo N. Can you teach old drugs new tricks? Nature. 2016;534(7607):314–6.
  53. Hampel H, Vergallo A, Aguilar LF, et al. Precision pharmacology for Alzheimer’s disease. Pharmacol Res. 2020;162:105349.
  54. Johnson CH, Ivanisevic J, Siuzdak G. Metabolomics: beyond biomarkers and towards mechanisms. Nat Rev Mol Cell Biol. 2016;17(7):451–9.
  55. Kim J, Campbell AS, de Ávila BE, Wang J. Wearable biosensors for healthcare monitoring. Nat Biotechnol. 2019;37(4):389–406.
  56. Saraiva C, Praça C, Ferreira R, Santos T, Ferreira L, Bernardino L. Nanoparticle-mediated brain drug delivery: overcoming blood–brain barrier to treat neurodegenerative diseases. J Control Release. 2016;235:34–47.
  57. Hölscher C. Central effects of GLP-1: new opportunities for treatments of neurodegenerative diseases. J Endocrinol. 2014;221(1):T31–41.
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