Neuronal function is strictly dependent on aerobic metabolism. When energy expenditure exceeds production, cellular dysfunction and ultimately cell death, or apoptosis, results. The specific cascade of molecular events relating to this process is termed excitoxicity.10,73
The initial event is traced to an oxidant stress and excessive stimulation of N-methyl-d-aspartate (NMDA) receptors by glutamate, an EAA neurotransmitter. An influx of intracellular calcium changes membrane potentials across the cellular and mitochondrial membranes. The mitochondria become progressively more inefficient at ATP production and handling the resulting reactive oxygen species. As membrane damage is propagated, calcium further depolarizes the mitochondria, activating a permeability transition pore across the mitochondrial membrane. Gradients are further disrupted, precipitating more injury, energy failure, and ultimately cell death.
Excitotoxicity is considered a common mechanism of cell death due to xenobiotic, ischemic, traumatic, infectious, neoplastic, or neurodegenerative injury. It is the subject of study for many therapeutic interventions in CNS injury.
Determinants of Neurotoxicity
The clinical expression of neurotoxicity is related to many factors. These include the chemical properties of the xenobiotic, the dose and route of administration, xenobiotic interactions, and underlying patient characteristics including age, gender, and comorbid conditions.
Chemical Properties of Xenobiotics
One of the most important determinants of neurotoxicity is the ability of a xenobiotic to penetrate the BBB. Water-soluble molecules larger than Mr200 to 400 (molecular weight ratio, or mass of a molecule relative to the mass of an atom) are unable to bypass the tight junctions.4 Xenobiotics with a high octanol/water partition coefficient are more likely to passively penetrate the capillary endothelium, and potentially the BBB, whereas those with a low partition coefficient may require energy-dependent facilitated transport.63 Xenobiotics that are substrates for capillary endothelial efflux mechanisms will have limited penetration regardless of the coefficient.1, 4, 52, 63
The route of xenobiotic administration may also be consequential. Although most xenobiotics gain access to the nervous system through the circulatory system, aerosolized solvent and heavy metals in industrial and occupational exposures gain CNS access through inhalation, traveling via olfactory and circulatory routes. Alternatively, some substances may move from the PNS via retrograde axonal transport to the CNS. Naturally occurring proteins such as tetanospasmin, as well as rabies, polio, and herpes virus may use this mechanism to access the PNS and CNS.13,16,47 The toxalbumins ricin and abrin as well as bismuth salts may also use this mechanism to a limited extent.85,91 This understanding may prove beneficial from a therapeutic perspective. For example, in one small experimental series of patients experiencing severe pain, doxorubicin was injected into the involved peripheral nerves. Therapeutically, a chemical ganglionectomy occurred through retrograde “suicide” transport of doxorubicin, which provided substantial relief for these patients.50
Some xenobiotics may be delivered directly into the CSF (intrathecally), the consequences of which are variable (Special Considerations: SC3).
Coadministration of xenobiotics may precipitate neurotoxicity by several mechanisms.45 Extraaxially (outside of the CNS), xenobiotic interactions that result in an increase of the blood concentration of one or both may overwhelm the protective mechanisms of the BBB.20 Similar effects may occur in the PNS where elevated blood concentrations may enhance clinical effects resulting in peripheral neuropathies.93
Xenobiotic interactions can be synergistic, acting on the same neuroreceptor. Benzodiazepines and ethanol, for example, both stimulate the γ-aminobutyric acid type A (GABAA) receptor. The excessive neuroinhibition can result in deep coma and even respiratory depression when these xenobiotics are administered simultaneously.
In some circumstances, xenobiotic interactions result in excessive neurotransmitter availability.9 This neurotransmitter excess is demonstrated in patients with the serotonin toxicity, which results from the coadministration of a monoamine oxidase inhibitor and a serotonin reuptake inhibitor or other serotonergics as an example (Chap. 75).
Access to the CNS may be altered by one of the xenobiotics, allowing the other to bypass the BBB. For example, mannitol causes transient opening of the BBB; as a result, therapeutic use of mannitol is under investigation for the delivery of chemotherapeutics that might otherwise be unable to access the nervous system.53 Similarly, some xenobiotics, such as verapamil, cyclosporine, and probenecid, are blockers of capillary endothelium efflux.4,93 These theoretically limit efflux of other substrates of P-glycoprotein or OAT. The clinical utility of employing such efflux blockers is under investigation as was done in a study in which primates received intrathecal methotrexate. The CSF clearance of methotrexate was reduced in animals administered intrathecal probenecid.12,76
Patient-specific variables may affect the ability of a xenobiotic to penetrate the BBB and/or the clinical effects of a given exposure. For example, age of the patient at the time of exposure is critical, especially in the fetus and neonates.78 The structural and enzymatic development of the BBB is incomplete, and synaptogenesis, or formation of intercellular relationships, is especially sensitive to impaired protein synthesis or other excitotoxic events. This is demonstrated classically by maternal exposure to methylmercury. The mother may be minimally affected, but the developing fetus suffers profound neurological and developmental consequences (Chaps. 31 and 98).
In neonates, immature liver function may lead to the accumulation of circulating bilirubin. Due to incomplete formation of the BBB, the bilirubin may access the CNS and produce a form of encephalopathy known as kernicterus.
Elderly patients may also have increased susceptibility to neurotoxins as a result of relatively impaired circulation or age-related changes in mitochondrial function that predispose to excitotoxicity.81 Xenobiotic-induced parkinsonism, or the unmasking of subclinical idiopathic Parkinson disease, may occur more readily than in younger patients. Animal models also suggest age-related sensitivity with one study noting increased manganese toxicity with advanced age.36
Gender may be contributory to the expression of xenobiotic-induced neurological injury. In animal models, the presence of estrogen-related and progesterone-related compounds may be neuroprotective for some xenobiotic injuries.64,71 In humans, women are more susceptible to some movement disorders such as xenobiotic-induced parkinsonism and tardive dyskinesia, whereas dystonias and bruxism are more prevalent in young men.74 The etiologies of these gender-related differences are incompletely understood.
Conditions affecting the integrity of the BBB can affect CNS penetration of xenobiotics and endogenous neurotoxins. For example, glutamate concentrations are normally higher in the circulatory system than the CNS.57 Patients with trauma, ischemia, or lupus vasculitis3 may experience neuropsychiatric disorders as a result of increased penetration of glutamate or sensitivity to additional xenobiotics. Similarly, inflammation associated with meningitis and encephalitis causes openings in the BBB, which may be exploited therapeutically. Intravenous penicillin achieves a higher CSF concentration in animals with meningitis than in those without meningitis.77
In some patients, previously undiagnosed diseases become evident on exposure to xenobiotics. This is especially true in patients with peripheral neuropathies. For example, patients being treated with therapeutic doses of vincristine suffered a severe polyneuropathy due to unmasking of a previously undiagnosed Charcot-Marie-Tooth disease.9,22 Similarly, patients with diabetes mellitus, the commonest cause of peripheral neuropathy, or human immunodeficiency virus disease may have exacerbation of symptoms in the presence of antiretrovirals.24,72 Patients with myasthenia gravis may have exacerbation of weakness with aminoglycoside administration, which can affect transmission at the neuromuscular junction (NMJ).92
Chronic exposures to some neuroinhibitory xenobiotics such as ethanol may alter neuronal receptor expression and upregulate or increase the amount of receptors for EAAs. In addition to receptor augmentation, neurotransmitter concentrations of the excitatory neurotransmitters glutamate and aspartate are increased, as is homocysteine. These changes induce a tolerance to neuroinhibitory xenobiotics acting on the same receptor, and patients require escalating doses to achieve the same clinical effect. In such patients, cessation of ethanol intake results in a relative deficiency of exogenous inhibitory tone. The patient experiences neuroexcitability and the clinical syndrome of withdrawal17,18 (Chap. 15).
Adequate nutritional status is important for the maintenance of normal neurological function. The BBB may not be adequately maintained in patients with malnutrition. Deficiencies of metal cofactors such as manganese, copper, zinc, and iron can affect neurological function. In some cases, the deficiencies enhance absorption of other xenobiotics. For example, iron deficiency enhances lead and manganese absorption in the gastrointestinal tract, which can ultimately overwhelm neuroprotective mechanisms. Vitamins serve as enzymatic cofactors in modulating the production of glutamate, homocysteine, and other amino acids. Specific vitamin deficiencies can precipitate neurological syndromes such as Wernicke encephalopathy in thiamine-depleted patients (Antidotes in Depth: A24 and Chap. 47). The toxicity of xenobiotics may also be enhanced. For example, a relative pyridoxine deficiency in patients with acute isoniazid overdose may result in seizures as a result of a relative excess of EAAs (Antidotes in Depth: A14 and Chap. 58). Glucose is a critical energy substrate that can cause profound neurological impairment when delivery is inadequate (Antidotes in Depth: A12 and Chap. 53).
Interestingly, certain conditions such as temperature may affect the toxicity of xenobiotics. For example, cooling may limit the impedance of acetylcholine neurotransmission caused by botulinum toxin.41
Extraaxial Organ Dysfunction
Kidney failure may impair metabolism or elimination of xenobiotics or endogenous neurotoxins such as urea, rendering it more available to the CNS. Hyperglycemia in patients with diabetes mellitus may also increase formation of CNS reactive oxygen species. Similarly, patients with liver failure may have elevations in CNS manganese resulting in Parkinsonism.51,79
Hepatic encephalopathy illustrates the concept of excitotoxicity from endogenous neurotoxins. Hyperammonemia increases oxidative stress and free radical formation in astrocytes. Ammonia potentially decreases critical metabolic enzymes such as catalases, superoxide dismutase, and glutathione peroxidase. Nitric oxide (NO) production is increased due to elevations in NO synthetase. Under these conditions, astrocytes upregulate the expression of the peripheral benzodiazepine receptor (PBR) on the outer mitochondrial membrane. The PBR modulates the production of neurosteroids and, in turn, the GABAA receptor. Continued CNS exposure to ammonia and other endogenous solutes propagates this oxidative and nitrosative stress to the mitochondrial membrane, potentially opening the mitochondrial permeability transition pore. Osmotic swelling of the mitochondrial membrane followed by excitotoxicity results in cerebral edema and hepatic encephalopathy.64, 65, and 66