What are the effects of pyrroloquinoline quinone on glutamate? And, can PQQ be used for neuroprotection?
Some of the earliest reports regarding the potential physiological functions of PQQ have involved studies focusing on PQQ and neural function and neuroprotection. In experimental animal models, the effects of pyrroloquinoline quinone on glutamate are mechanisms that protect the redox modulatory site of so-called “glutamate receptors”. Glutamate receptors are located primarily on the membranes of neuronal cells. This class of receptors is responsible for glutamate-mediated excitation of neural cells that are important for neural communication, memory formation, learning, and regulation.
Glutamate is the most prominent neurotransmitter in the body. The common name for the two primary glutamate receptors actually derives from the chemical names of two agonists used to study them, i.e., the AMPA receptor that binds to both glutamate and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and the NMDA receptor that binds to both glutamate and N-methyl-D-aspartate or NMDA. An agonist is a chemical that binds to a receptor of a cell and triggers a response in a cell similar to that of the native or more physiological receptor.
In many of the studies, the N-methyl-D-aspartic acid (NMDA) receptor has received the most attention. It is a specific type of glutamate receptor involved in ion-transport. Agents that protect NMDA-receptor function are often neuroprotective. With regard to PQQ, exposure to PQQ either in vitro or in vivo has been shown to promote the recovery of from spinal cord injury in rats after hemi-transection (Hirakawa et al. Biochem Biophys Res Commun. 2009; 378:308-12) and counteract the effects of potent neurotoxins, such as 6-hydroxydopamine (Hara et al. Neurochem Res. 2007; 32:489-95). A number of studies have also shown that PQQ can act as a neuroprotectant in animal models of stroke therapy and ischemic stroke (Zhang et al. Brain Res. 2006; 1094:200-206; Zhang et al. Eur J Neurosci. 2002; 16:1015-1024; Aizenman et al. J Neurosci. 1992; 12:2362-9; Jensen et al. Neuroscience. 1994; 62:399-406; Scanlon et al. Eur J Pharmacol. 1997; 326:67-74). A very interesting feature relates to the promotion of nerve regeneration of transected nerves when tissue damage/repair is involved (Li et al. Chin J Traumatol. 2005; 8:225-229; Lui et al. Microsurgery 2005; 25:329-337). When one couples this in formation to that which indicates PQQ and some of its derivatives can stimulate nerve growth factor synthesis, it indicates a very promising potential for the use PQQ in correcting damage to neural tissue (Murase et al. Biosci Biotechnol Biochem. 1993; 57:1231-1233; Urakami et al. Biofactors. 1995-1996; 5:139-146).
Neurological manifestations caused by neural injury may also be influenced by PQQ. For example, protection of the NMDA receptor redox modulatory site by PQQ has been shown to improve the pathophysiology of seizures. Rat pups with chemically induced convulsions and seizures are protected by PQQ administration (Sanchez et al. J Neurosci. 2000; 20:2409-2417). All of these observations are promising, although a direct link to human disease needs to be made. All of the studies to date have utilized rodent models.
How is neuronal protection achieved?
With regard to damaged nerve fibers, several studies suggest PQQ can protect against secondary damage by reducing the expression or production of the enzyme, nitric oxide syntheses (NOS), following a primary physical injury to the nerve. NOS enzyme activity and its major product are essential to nerve function. Low levels of nitric oxide production, the product from an NOS reaction, are important in protecting an organ from oxidant damage. However, one can also relate its activity to nerve damage in the following way. First, similar to other tissues, following injury or damage, increased amounts of reactive oxygen species (ROS) are often produced. Some of these ROS products can react with nitric oxide to form peroxynitrite as an additional potential by-product. Although nitric oxide (produced by the action of NOS) is an important cellular signaling molecule, its product, peroxynitrite, resulting from the reaction of NO with ROS is a compound with potent damaging oxidant potential. Thus, the demonstration that inducible NOS expression and peroxynitrite formation is depressed or decreased by PQQ is one potential mechanism for PQQ’s action (Zhang & Rosenberg. Eur J Neurosci. 2002; 16:1015-24; Hirakawa et al. Biochem Biophys Res Commun. 2009; 378:308-12).
Moreover, PQQ’s ability to influence the levels of the cell signaling molecule, DJ-1, adds an additional dimension. DJ-1 is a neuronal cell-signaling molecule and plays a role in oxidative stress reactions important to optimizing neurological function and protecting against inappropriate cell death. DJ-1 has also been shown to be the same protein as PARK7 (Parkinson disease autosomal recessive, early onset 7), which has been implicated in early onset Parkinson’s disease. PQQ increases the level of an active form of DJ-1 (Nunome et al. Biol Pharm Bull. 2008; 31:1321-6). As this information develops as well as that related to the effects of PQQ on other signaling molecules, it should soon be possible to extract a precise mechanism of action. For example, it has recently been shown that the glutamate-induced apoptosis (early cell death) in cultured neurons is significantly reversed by PQQ treatment. In addition, examination of several key cell-signaling molecules, which work in tandem with components of the glutamate receptor signaling pathways, has revealed that PQQ treatment stimulates their activation (Zhang et al. Toxicol Appl Pharmacol. 2011; 252:62-72).
What does mean to the consumer of supplements?
First, as pointed out in our other discussions. A compound may be a good “chemical” antioxidant in assays in vitro, but do little to improve a pathophysiological condition in vivo. Cellular antioxidant activity is mostly controlled by the regulation of metabolic processes (mostly enzymes) that in turn are highly regulated by events that take place in complex and interactive cell signaling pathways. PQQ is know now known to influence a number of these pathways neuronal cells at relatively low levels of intake. Whether PQQ has any clinical efficacy in the treatment of stroke, Parkinson’s disease, or any of the mitochondrial-related neurological diseases remains to be seen. However, many investigators are excited about the potential of this prospect given the positive responses to PQQ in experimental models of neurological disease.