Caffeine, a natural methylxanthine nutraceutical, exerts dopaminergic neuroprotection

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects more than 10 million people worldwide. Oxidative stress and mitochondrial dysfunction play a significant role in altering the homeostasis of energy production and free radical generation. Current PD therapies are focused on reducing the cardinal symptoms rather than preventing disease progression in the patients. Adenosine A2A receptor (A2A R) antagonist (Istradephylline) combined with levodopa shows a promising therapy for PD. In animal studies, caffeine administration showed to improve motor functions and neuroprotective effect in the neurons. Caffeine is probably the most extensively used psychoactive substance. In this current study, the neuroprotective effect of caffeine was investigated against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration [1]. It was demonstrated that caffeine improves behavioral and neurotransmitter recovery against MPTP-induced toxicity. Caffeine restores endogenous antioxidant levels and suppresses neuroinflammation. The findings suggest that the blockage of A2AR is a promising disease-modifying therapy for PD. Target engagement strategies could be more beneficial in preventing disease progression rather than symptomatic reliefs in PD patients.

The cyclodextrin-caffein interaction was studied by several research groups. The association constant (700 M-1 [2] and 400 M-1 [3] determined by phase-solubility and fluorimetry, resp.) for HPBCD/caffeine complex was published. The association constant for BCD/caffein complex was found much lower (171 M-1 [3] and 30 M-1 [4] by fluorimetry and by calorimetry, resp.).

The low affinity of BCD to caffein can explain the controversial results on the decaffeination of model coffee extracts by BCD or BCD polymer [5, 6].

References

[1] Senthilkumar S. Karuppagounder, Subramaniam Uthaythas, Manoj Govindarajulu, Sindhu Ramesh, Koodeswaran Parameshwaran, Muralikrishnan Dhanasekaran (2021) Caffeine, a natural methylxanthine nutraceutical, exerts dopaminergic neuroprotection. Neurochemistry International 148,105066.
https://doi.org/10.1016/j.neuint.2021.105066.

[2] Krishnamoorthy R., Wolka A., Mitra A.K. (1993) Complexation of weak bases with cyclodextrins: estimation and interpretation of association constants from phase solubillity diagrams. AAPS Eight Annual Meeting, Lake Buena Vista, Florida, USA, Nov 14- 18

[3] Wei, YL Ding, LH Dong, C Niu, WP Shuang, SM (2003) Study on inclusion complex of cyclodextrin with methyl xanthine derivatives by fluorimetry. Spectroc. Acta Pt. A-Molec. Biomolec. Spectr., 59(12), 2697-2703.

[4] Terekhova, I. V., & Kulikov, O. V. (2002). Calorimetric study of the molecular recognition of nucleic acid bases by β-cyclodextrin in aqueous solution. Mendeleev Communications, 12(6), 245–246. https://doi.org/10.1070/mc2002v012n06abeh001648

[5] Shaw, P.E., Buslig, B.S. (1986) Selective removal of bitter compounds from grapefruit juice and from aqueous solution with cyclodextrin polymers and with Amberlite XAD-4. J. Agric. Food Chem., 34(5), 837-840.

[6] Yu, E.K.C. (1988) Novel decaffeination process using cyclodextrins. Appl. Microbiol. Biotechnol. 28, 546-552. https://doi.org/10.1007/BF00250410