Neurotoxin - Background

Background

Exposure to neurotoxins in society is not new as civilizations have been exposed to neurologically destructive compounds for thousands of years. One notable example is the possible significant lead exposure during the Roman Empire resulting from the development of extensive plumbing networks and the habit of boiling vinegared wine in lead pans to sweeten it, the process generating lead acetate, known as "sugar of lead". In part, neurotoxins have been part of human history because of the fragile and susceptible nature of the nervous system, making it highly prone to disruption.

The nervous tissue found in the brain, spinal cord, and periphery comprises an extraordinarily complex biological system that largely defines many of the unique traits of individuals. As with any highly complex system, however, even small perturbations to its environment can lead to significant functional disruptions. Properties leading to the susceptibility of nervous tissue include a high surface area of neurons, a high lipid content which retains lipophilic toxins, high blood flow to the brain inducing increased effective toxin exposure, and the persistence of neurons through an individual's lifetime, leading to compounding of damages. As a result, the nervous system has a number of mechanisms designed to protect it from internal, and external insults, including the blood brain barrier.

The blood brain barrier (BBB) is one critical example of protection which prevents toxins and other adverse compounds from reaching the brain. As the brain requires nutrient entry and waste removal, it is perfused by blood flow. Blood can carry a number of ingested toxins, however, which would induce significant neuron death if they reach nervous tissue. Thus, protective cells termed astrocytes surround the capillaries in the brain and absorb nutrients from the blood and subsequently transport them to the neurons, effectively isolating the brain from a number of potential chemical insults.

This barrier creates a tight hydrophobic layer around the capillaries in the brain, inhibiting the transport of large or hydrophilic compounds. In addition to the BBB, the choroid plexus provides a layer of protection against toxin absorption in the brain. The choroid plexuses are vascularized layers of tissue found in the third, fourth, and lateral ventricles of the brain, which through the function of their ependymal cells, are responsible for the synthesis of cerebrospinal fluid (CSF). Importantly, through selective passage of ions and nutrients and trapping heavy metals such as lead, the choroid plexuses maintain a strictly regulated environment which contains the brain and spinal cord.

By being hydrophobic and small, or inhibiting astrocyte function, some compounds including certain neurotoxins are able to penetrate into the brain and induce significant damage. In modern times, scientists and physicians have been presented with the challenge of identifying and treating neurotoxins, which has resulted in a growing interest in both neurotoxicology research and clinical studies. Though clinical neurotoxicology is largely a burgeoning field, extensive inroads have been made in the identification of many environmental neurotoxins leading to the classification of 750 to 1000 known potentially neurotoxic compounds. Due to the critical importance of finding neurotoxins in common environments, specific protocols have been developed by the Environmental Protection Agency (EPA) for testing and determining neurotoxic effects of compounds (USEPA 1998). Additionally, in-vitro systems have increased in use as they provide significant improvements over the more common in-vivo systems of the past. Examples of improvements include tractable, uniform environments, and the elimination of contaminating effects of systemic metabolism. In-vitro systems, however, have presented problems as it has been difficult to properly replicate the complexities of the nervous system, such as the interactions between supporting astrocytes and neurons in creating the BBB. To even further complicate the process of determining neurotoxins when testing in-vitro, neurotoxicity and cytotoxicity may be difficult to distinguish as exposing neurons directly to compounds may not be possible in-vivo, as it is in-vitro. Additionally, the response of cells to chemicals may not accurately convey a distinction between neurotoxins and cytotoxins, as symptoms like oxidative stress or skeletal modifications may occur in response to either.

In an effort to address this complication, neurite outgrowths (either axonal or dendritic) in response to applied compounds have recently been proposed as a more accurate distinction between true neurotoxins and cytotoxins in an in-vitro testing environment. Due to the significant inaccuracies associated with this process, however, it has been slow in gaining widespread support. Additionally, biochemical mechanisms have become more widely used in neurotoxin testing, such that compounds can be screened for sufficiency to induce cell mechanism interference, like the inhibition of acetylcholinesterase capacity of organophosphates (includes DDT and sarin gas). Though methods of determining neurotoxicity still require significant development, the identification of deleterious compounds and toxin exposure symptoms has undergone significant improvement.