Table 1.
Summary of the preclinical studies that evaluate the neuroprotective effects of caffeine in the treatment of PD. Specifically, the table lists the animal models used in the studies, the type of treatment, the dosage and the therapeutic effects obtained.
| Animal Models | Induced PD Models | Treatment | Dosage and Route of Administration | Therapeutic Effects | Ref. |
|---|---|---|---|---|---|
| C57BL/6 mice | MPTP (single dose 40 mg/kg) or (multiple-dose 20 mg/kg) via intraperitoneal | Caffeine and A2AR antagonists | 0–60 mg/kg via intraperitoneal 10 min before injury | Caffeine reduced MPTP-induced dopamine depletion, improving the locomotor activity. Caffeine exerts its action blocking the A2ARs, as demonstrated by using mice lacking the A2AR. The treatment with A2AR antagonists also confirmed this result. | [96] |
| male Sprague–Dawley rats | MPTP (75 μg/ day) unilateral intra-cerebroventricular infusion for 28 days | Caffeine | 60–80 mg/kg daily, after 1 to 3 weeks from the injury | After 7 and 21 days of caffeine administration, mice treated with MPTP showed a reduction in the loss of nigrostriatal dopamine neurons and the response of microglia in the substantia nigra, with a consequent decrease in neuroinflammation. | [75] |
| FVB mice | MPTP (20 mg/kg) daily via intraperitoneal for the second week | Caffeine | 10 mg/kg via intraperitoneal for the first 7 days and 10 min before MPTP treatment for the second week | The pretreatment with caffeine prevented the damage to the BBB induced by MPTP and decreased the activation of astrocytes and microglia. | [97] |
| Swiss albino mice | MPTP (20 mg/kg) daily for the subsequently 4 weeks | Caffeine and nicotine | Caffeine (20 mg/kg) and nicotine (1 mg/kg), via intraperitoneal, daily for the first 8 weeks | The consumption of caffeine restored the transcription of genes involved in several processes, including cell apoptosis, cell cycle regulation and oxidative stress. These transcripts were downregulated in MPTP mice. | [98] |
| Swiss albino mice | MPTP (20 mg/kg) from 1 day to 4 weeks | Caffeine and nicotine | Caffeine (10–30 mg/kg) and nicotine (0.5–1.5 mg/kg) pretreated daily via intraperitoneal for 8 weeks | Caffeine (20 mg/kg) or nicotine (1 mg/kg) treatments prevented the depletion of dopamine induced by MPTP. Both alkaloids reduced the expression of GSTA4-4, GST-ya, GST-yc and VMAT-2, reducing the MPTP-induced toxicity. | [99] |
| Wistar rats | 6-OHDA (12 μg/μL) single stereotaxic injection | Caffeine | 10 and 20 mg/kg via intraperitoneal for 13 days, one hour after injury | Caffeine prevented the MPTP-induced dopamine and DOPAC depletion. In this way, caffeine improved motor deficits. | [100] |
| Wistar rats | 6-OHDA (12 μg/μL) stereotaxic injection into the right corpus striatum | CSC and L-DOPA | Caffeine 1–5 mg/kg and L-DOPA (50 mg/kg + benserazide 12.5 mg/kg) administered alone or co-administered for 7 consecutive days | The CSC prevented dopamine depletion and DOPAC, 6-OHDA-induced. The CSC treatment promoted a decrease in monoamines, enhancing its neuroprotective effect. The effects of CSC were potentiated when administered together with L-DOPA. | [101] |
| C57BL/6 mice | 6-OHDA (2.5 μg/μL) unilaterally into the left dorsal corpus striatum | Caffeine and L-DOPA | Caffeine (2.5 or 10 mg/kg) and L-DOPA (2.0 mg /kg) administered alone via intraperitoneal after the injury for 14–21 days, or co-administered at higher dosage for 26 days |
The treatment of caffeine associated with L-DOPA led to an improvement in sensitized rotational behavior in mice induced with 6-OHDA compared to control mice. | [102] |
| Wistar rats | 6-OHDA (0.2 μL/min) unilaterally into the substantia nigra | Caffeine and SCH 5826 | Caffeine (30 mg/kg) and SCH 58261 (2 mg/kg) via intraperitoneal |
The treatment with caffeine led to an improvement in balance disorders in mice treated with 6-OHDA. These results could be obtained through the inhibition of presynaptic A2AR, as demonstrated by the use of its antagonist, SCH 58261. | [103] |
| Long Evans rats | 6-OHDA (12 μg) unilaterally via intraperitoneal | Caffeine, SCH 5826, L-DOPA, N6-Cyclopentyladenosine and 8-Cyclopentyltheophylline | Caffeine (15 mg/kg), SCH 58261 (2 mg/kg), L- DOPA (8 mg/kg) N6-Cyclopentyladenosine (0.03–0.2 mg/kg) and 8-Cyclopentyltheophylline (3–7 mg/kg) via systemic intraperitoneal |
The caffeine treatment associated with L-DOPA in rats induced with 6-OHDA improved the motor activity. These improvements could be obtained through the inhibition of A2AR, as demonstrated by the use of its antagonist SCH 5826. | [104] |
| Sprague Dawley rats | 6-OHDA (2 μg/μL) unilateral infusion into the nigrostriatal | L-DOPA, Caffeine, SCH 412348, Istradefillin and Vipadenant | L-DOPA (6 mg/kg), Caffeine (30 mg/kg), SCH 412348 (3 mg/kg), Istradefillin (3 mg/kg) and Vipadenant (10 mg/kg) after 14 days from the injury with L-DOPA and A2AR antagonists for 19–22 days |
Chronic treatment with caffeine or A2AR antagonists (SCH 412348, vipadenant, or istradefillin) does not induce dyskinetic activity in rats treated with 6-OHDA, unlike L-DOPA. | [105] |
| C57BL/6 (A1−/−, A2A+/+) KO, (A1+/+, A2A−/−) KO and (A1−/−, A2A−/−) KO mice |
6-OHDA (10 μg) stereotactic unilateral injection | Caffeine and L-DOPA | Caffeine (3–15 mg/kg) and L-DOPA (2 mg/kg) via intraperitoneal with L-DOPA for 2–3 weeks after 14 days from the injury and 10 min before the administration of L-DOPA with two doses intraperitoneal of caffeine | Caffeine did not alleviate L-DOPA-induced dyskinesia, probably due to its general motor stimulation actions. The simultaneous blocking of A1R and A2AR, like caffeine, did not improve dyskinesia compared to the use of a specific A1R or A2AR antagonist alone. | [106] |
| Wistar rats | ROT (1.5 mg/kg) via intraperitoneal for 45 days | Caffeine | 30 mg/kg before or after the induction of ROT | Caffeine treatment restored dopamine levels in the corpus striatum and prevented motor and muscle deficits induced by ROT. Caffeine reduced the level of MDA and oxidative stress. | [107] |
| C57BL/6NCrl mice | PQ (10 mg/kg) and MB (30 mg/kg) via intraperitoneal 10 min after caffeine treatment | Caffeine | 5 or 20 mg/kg via intraperitoneal | Caffeine treatment prevented the neurodegeneration of dopaminergic neurons induced by chronic pesticide exposure. | [108] |
| Wistar rats | Reserpine (5 mg/kg) via intraperitoneal | Caffeine and THP | Caffeine (1 mg/kg) and THP (0.1 mg/kg), 24 h after the injury, the animals were treated alone with caffeine or THP, or caffeine and THP combined | In reserpine-induced rats, the co-treatment of caffeine and THP led to the recovery of motor and exploratory activities. The treatments with caffeine or THP did not invert hypokinesia induced by reserpine. | [111] |
MPTP: N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; A2AR: adenosine 2A receptor; DMPX: 3,7-dimethyl-1-propargylxanthine; KW-6002: istradefylline; BBB: blood brain barrier; PD: Parkinson’s Disease; 6-OHDA: 6-hydroxydopamine; DOPAC: 3,4-dihydroxyphenylacetic acid; CSC: 8-(-3-chlorostyryl)-caffeine (CSC); L-DOPA: L-3,4-dihydroxyphenylalanine; AIMs: abnormal involuntary movements; KO: knockout; A1−/−, A2A+/+: A1R KO; A1+/+, A2A−/−: A2AR KO; A1−/−, A2A−/−: A1R-A2AR KO; ARs: adenosine receptors; A1R: adenosine 1 receptor; ROT: rotenone; MDA: malondialdehyde; SOD: superoxide dismutase; PQ: paraquat; MB: maneb; GSH-S-transferase: glutathione-S-transferase; THP: trihexyphenidyl.