Pyrroloquinoline quinone (PQQ) is a small molecule that was once considered a vitamin, although its role in the human body is unrelated to this hypothesized vitamin-like mechanism. Through its role as a REDOX (oxidation-reducing agent) agent in cells, it modifies signal transduction and is thought to support mitochondrial function.

Pyrroloquinoline quinone is a small quinone molecule that has the ability to become a REDOX agent, capable of reducing oxidants (antioxidant effects) and then recycling back into the active form via glutathione. It seems to be very stable because it can go through thousands of cycles before it runs out.

It is a coenzyme in bacteria (so, for bacteria, this is like a B vitamin), but this role does not seem to extend to humans. Since this does not extend to humans, the designation of PQQ as a vitamin compound has fallen through, and it is only considered "vitamin-like".

For human evidence, we now have limited evidence that there may be a neuroprotective effect in the elderly (there is no study of the clinical condition of neurodegenerative diseases, and there are no studies), it may have an anti-inflammatory effect. This limited evidence also suggests that the main requirement of PQQ, the enhancement of mitochondrial function, occurs in otherwise healthy humans who supplement PQQ.

Animal evidence that may be applicable to humans (using oral supplements at doses similar to those used in humans), including radiation protection effects, may be beneficial for insulin resistance, and is a growth factor when PQQ is added to the diet long-term. Higher-than-normal oral doses in rodents also seem to enhance peripheral neurogenesis (nerve growth outside the brain), but not necessarily the brain.

Substantial evidence of direct antioxidant effects or neurological effects associated with NMDA signaling of PQQ appears to be used in cells at very high concentrations, possibly due to possible transport problems in the brain and low concentrations of PQQ found in the blood after oral ingestion.

Since total deprivation from the animal diet has been shown to hinder growth and reproductive performance, it was initially thought that this (combined with initial speculation of endogenous synthesis via AASDH) indicated vitamin deficiency. However, because the definition of the vitamin is that a disease state needs to occur during a deficiency, and there is no significant dysfunction other than the impaired growth seen in PQQ deficiency, it is not classified as an essential vitamin.

PQQ has been studied as a growth factor in young people (because deprivation impures growth in rats), secondary to its effect of improving mitochondrial biogenesis (producing more mitochondria) at seemingly effective doses of 0.2-0.3mg/kg food (in mice), surprisingly close to levels found in human breast milk. Preliminary evidence of mitochondrial efficacy has also been noted in the adult population at 0.075-0.3mg/kg per day, the latter at doses close to the recommended daily dose of 20mg for adults.

PQQ is considered a non-vitamin growth factor, in part due to its naturally high levels in breast milk and reduced growth in rats without PQQ in their diet.

PQQ injection into the brain is known to have neuroprotective effects, but it is unclear whether this also applies to oral ingestion. Rotenone is a commercial insecticide that inhibits electron transfer in mitochondria, resulting in high levels of reactive oxygen species production, oxidative damage, and cell death through apoptosis. Based on these properties, rotenone is often used in rodent models of Parkinson's disease, where chronic infusion causes oxidative damage, similar to many features of the human disease. A recent study examined the ability of PQQ to confer neuroprotective effects in rotenone-induced models of Parkinson's disease. By changing the balance of pro-vs, SH-SY5Y neuroblastoma cells were treated with 100μMPQQ to protect them from rotenone-induced apoptosis. Anti-apoptotic proteins that promote cell survival by reducing oxidative damage.

Although rotenone alone reduced mitochondrial mass by 36%, PQQ pretreatment further protected mitochondria, keeping mitochondrial mass close to control levels. In rotenone-induced models of Parkinson's disease, rotenone is usually injected directly into the brain, causing neuronal damage that approximates the pathology of the human disease. Importantly, the in vitro effects of PQQ were validated in vivo, where PQQ injected directly into the brain with rotenone reduced neuronal damage and improved symptoms.

PQQ has been shown to be protective in rodent models of Parkinson's disease. In vitro studies have further shown that this protective effect occurs by reducing oxidative stress and protecting mitochondria, inhibiting cell death. More research is needed to determine the effect of PQQ on Parkinson's disease in humans.

In isolated mouse astrocytes, it exceeded alpha-lipoic acid (ALA) in potency, but was lower than ALA in c/3T3 (embryonic fibroblast) cells, and an increase in NGF synthesis was also noted.

When the fat-soluble derivative (PQQ trimethyl ester) was injected every other day with 0.1-1mg/kg, enhanced regeneration of the peripheral sciatic nerve was noted. Peripheral injection did not cause an increase in NGF. The neocortex is thought to be due to poor diffusion of PQQ in the blood-brain barrier due to protein compounding in the serum. Drug modification of the PQQ enzyme enhances brain NGF concentrations, and because OPQ is known to be metabolized to PQQ in bacteria (hypothesized to occur in rodents) and is fat-soluble, it is thought to act as a precursor.

When tested later, PQQ added to silicone tubes confirmed an increased rate of physical recovery in a mouse model of physical nerve injury, with benefits visible after four weeks of extension to 12 weeks. This improvement was associated with an increase in good myelin neurons.

In a spinal cord injury model, a daily injection of 5mg/kg of PQQ for one week after injury was able to inhibit iNOS expression (a biomarker of inflammation) and improve motor performance and neuronal health (axon density) relative to control areas one day later. Benefits on peripheral nerve function have been noted (in rat models with sciatic nerve injury); A low dose (20mg/kg) prevented hyperalgesia caused by nerve damage, while only a higher dose (40mg/kg) prevented muscle atrophy and lipid peroxidation.

When injected with 10mg/kg 30 minutes before ischemia, pyrroloquinoline quinone (PQQ) appeared to have a protective effect against ischemia (as assessed by jaw size) (reducing infarct size from 95 +/ -3.6% to 68.8 +/ -10.4%). It was also slightly less effective after immediate injection rather than preloading (the previous reduction of 37.6% was reduced to a reduction of 18.5%). This has been replicated in other studies at 3-10mg/kg (70-81% protection).

Another human study found that PQQ had a modest but significant effect on cognitive function in older adults with spatially impaired vision. Since cognitive function inevitably declines with age, the purpose of the study was to examine whether PQQ could help maintain or improve cognitive function in older adults. To examine whether PQQ can enhance cognitive function, 42 individuals with an average age of 58 years were assigned to placebo or PQQ supplementation in randomized, placebo-controlled and double-blind trials. Subjects were given 20mg of PQQ disodium salt (BioPQQ, manufactured by Mitsubishi Gas Chemical Co., Tokyo, Japan) or placebo every day after breakfast for 12 weeks. The Stroop test, the reverse Stroop test, and the Touch M test (a laptop tablet test used to assess visual-spatial cognitive function) were administered at week 0 to establish baseline/pre-supplement cognitive function, and the effects of supplementation were assessed at week 12. For Stroop or reverse Stroop tests, there was no significant difference between the PQQ group or placebo. In contrast, the Touch M test showed some differences, where higher scores indicated higher function, while scores less than 70 reflected a decline in brain function. While patients with an average baseline Touch M score greater than 70 did not show a significant difference after 12 weeks of PQQ supplementation, individuals with an initial Touch M score less than 70 increased significantly from 58.1 at baseline to 71.5 after 12 weeks of supplementation. While more research is needed to verify this result in other subjects, at face value, this work suggests that PQQ may help restore some of the lost cognitive abilities in older adults with impaired cognitive function. However, this work is preliminary and will require further investigation until any definitive conclusions are reached.

An open human study of 17 people with fatigue or sleep disorders at 20 weeks of PQQ showed that PQQ was able to significantly improve sleep quality, and improvements in sleep duration and quality occurred during the first test period after 4 weeks of use, although it took 8 weeks for the reduction in sleep latency to become significant. The study also suggests that improved appetite, concentration, and pain rating may be secondary factors to improved sleep; Life satisfaction tended to increase but did not reach a significant level within 8 weeks.

Premitochondrial effects and antioxidant effects secondary to ischemia/reperfusion, PQQ appears to have cardioprotective effects in some cases.

Oral intake of 4mg/kg PQQ to mice (more effective than 2mg/kg and 8mg/kg, and more effective than the reference drug 10mg/kg neilestrol) appears to reduce death from gamma radiation, given one hour before exposure and again after exposure for 7 days; Damage to the selected cells (leukocytes, reticulocytes, bone marrow cells) was also reduced with the supplementation of 4mg/kg PQQ in mice. Oral ingestion of PQQ (estimated to be equivalent to 0.32mg/kg in humans) appears to protect mice from gamma exposure to a considerable degree.

PQQ is involved in reducing the expression of the melanogenic (melanin-producing) protein in cultured B16 cells, where it inhibits tyrosinase expression and reduces gene activity, and can prevent alpha-melanocyte stimulating hormone from stimulating trypsin mRNA.

Rats fed the PQQ-deficient diet with the same diet fed 2mg/kg PQQ had a 20-50% increase in plasma diglycerides and triglycerides (DAG and TAG) in the PQQ-deficient diet relative to 2mg/kg PQQ (higher values associated with triglycerides). There were no significant differences in free fatty acids, which are similar to levels previously seen in this experimental protocol. Elevated triglycerides in deficient mice did not affect the n3 / n6 omega fatty acid ratio.

Pyrroquinone appears to inhibit amyloid fibrillary formation (Aβ1-42; Completely inhibited at 70μM PQQ), although it can also bind to α-synuclein, this binding does not indirectly inhibit Aβ1-42 aggregation. PQQ can reduce the cytotoxicity of these fibril to nerve cells.

Therapeutic dose

The optimal daily dose of pyrroloquinoline quinone is currently unknown, but inference from animal studies suggests that doses as low as 2mg have some biological activity, while most dietary supplements are sold at 20-40mg.