Gamma-aminobutyric acid

Gamma-aminobutyric acid (GABA) is produced by GABAergic neurons and is the most common inhibitory neurotransmitter in the central nervous system. As a neurotransmission inhibitor, GABA acts as an electrochemical resistance to lessen the ability of a nerve cell to receive, create, or convey electrical charge signals to other nerve cells. the GABA- benzodiazepine receptor complex inhibits neurotransmission, thereby producing a calming effect to suppress symptoms. For the GABA-benzodiazepine receptor complex to be established, GABAergic excitation and thereby the production of GABA is a prerequisite.

What is less known is that GABA also has a parallel inhibitory role in the immune system. The immune system harbors necessary constituents for GABA signaling, and GABA itself participates as a paracrine/autocrine factor at the site of inflammation. GABA’s paracrine and autocrine properties respond to neuroinflammation in addition to directly resisting neurotransmission in neurons exhibiting these pro-inflammatory cytokines. Through pro-inflammation, GABA can selectively target stressed neurons. Immune cells responding to the inflammation synthesize GABA and possess mechanisms for GABA catabolism. Antigen-presenting cells (APCs) express functional GABA receptors and can electrophysiologically respond to GABA. These findings suggest that inflammation is a primary trigger for GABAergic activation.

Neuroinflammatory GABAergic excitation

Persistent neuroinflammation is a major pathological component of virtually all neurodegenerative diseases and has also been a focus of research into the pathology underlying psychiatric disorders. Research evidence suggests that neuroinflammation induces changes in the GABA neurotransmitter system within the CNS and that GABAergic signaling exerts a reciprocal influence over neuroinflammatory processes.

Neuroinflammation is key to GABAergic excitation. Hypothetically the GABA system is a potential therapeutic target in the modulation of central inflammation. This is particularly true for neurodegenerative conditions that have origins resulting in inflammation first, such as circulatory disorders, autoimmunity, or physical injuries where the self-modulation principles of neuroprotective GABA are essential for specific purposes of damage control.

On the other hand, when GABAergic excitation is to be directly induced to achieve quick symptomatic relief in an otherwise non-inflammatory brain, the chemical administered needs to first trigger neuroinflammation to achieve GABAergic excitation. Two common examples of chemically induced GABAergic excitation are heavy metal poisoning and benzodiazepine action. Chemically induced neuroinflammation is different from natural injuries wherein the chemical entity may be constantly added and has a systemic impact. In the central nervous system (CNS), glial cells display immunological responses to pathological and physiological stimuli through pro- and anti-inflammatory cytokine and chemokine signaling, antigen presentation, and the clearing of cellular debris through phagocytosis. While this neuroinflammatory signaling can act to reduce neuronal damage and comprises a key facet of CNS homeostasis, persistent inflammation from chemical exposure or auto-antigen-mediated immunoreactivity can induce a positive feedback cycle of neuroinflammation that ultimately results in necrosis of glia and neurons.

Excitotoxicity

Artificially (Chemically) triggering GABAergic activity has been shown to ameliorate ongoing paralysis in experimental autoimmune encephalomyelitis (EAE) by inhibiting inflammation, despite GABA’s immunomodulatory purpose which in this case affects adversely. The effect here is demyelination. GABAergic agents act directly on APCs, decreasing MAPK signals and diminishing subsequent adaptive inflammatory responses to myelin proteins. This particular mechanism obstructs oligodendrocyte signaling, leaving neurons exposed to extended periods of undesirable electrical leakage and a chain reaction of electrochemical abnormalities follows. Demyelination in the central nervous system forces a state of excessive neurotransmission through the remainder of the CNS, causing those neurons to carry excessive loads of electrical current. Neurons functioning over-capacity keep adding to the pro-inflammation. This state of neurons is known as excitotoxicity.

Benzodiazepine dependency

Benzodiazepines are highly addictive CNS depressants that act by tranquilizing and are not meant for regular use. Benzodiazepines, like heavy metals and many other sedative-hypnotic drugs, cause apoptotic neuronal cell death. However, benzodiazepines do not cause as severe apoptosis in the developing brain as alcohol does. The prenatal toxicity of benzodiazepines is most likely due to their inflammatory effects on neurotransmitter systems, cell membranes, and protein synthesis. This, however, is complicated in that the neuropsychological or neuropsychiatric effects of benzodiazepines, if they occur, may not become apparent until later childhood or even adolescence. A review of the literature found current data on long-term follow-up regarding neurobehavioral outcomes is very limited.

Consistent use of benzodiazepines leads to the development of benzodiazepine dependence and tolerance. Once the excitotoxic cycle is entered, a subject will yearn for relief from the increasing neuroinflammatory discomfort. Abruptly withdrawing from the drug will cause a GABAergic downregulation and thereby enhance the excitotoxic symptoms due to reattempted stimulations by the brain. Benzodiazepine dependence can therefore be categorized as a pain-driven dependence rather than a pleasure-driven dependence.

Benzodiazepine Toxicity

The classic presentation in patients with extended, isolated benzodiazepine exposure will include central nervous system (CNS) depression with normal or near-normal vital signs. Many patients will still be arousable and even provide a reliable history. Classic symptoms include slurred speech, ataxia, altered mental status, and hormonal disorders. Respiratory compromise is uncommon in isolated benzodiazepine ingestions, but if taken with coingestants such as ethanol or other drugs/medications, respiratory depression can be noted. It is important to note that most intentional ingestions of benzodiazepines do involve coingestants, the most common being ethanol, leading to substantial respiratory depression and airway compromise. The dose required to produce respiratory compromise is difficult to quantify and depends on multiple factors, including dosage, tolerance, weight, age, coingestants, and even genetics. Patients with severe toxicity will present in a stuporous or comatose state, and immediate airway management and mechanical ventilation may be required.

A unique toxidrome related to parenteral formulations of diazepam and lorazepam is propylene glycol poisoning. Propylene glycol is the diluent used in the parenteral formulations for these two benzodiazepines, and prolonged use can cause propylene glycol toxicity, which includes skin and soft tissue necrosis, hemolysis, cardiac dysrhythmias, hypotension, significant lactic acidosis, seizure, and multisystem organ failure. While propylene glycol toxicity is rare, it must be considered when patients are receiving large or continuous infusions of parenteral benzodiazepines, for example, when treating severe sedative or ethanol withdrawal syndromes such as delirium tremens.

Significant toxicity from benzodiazepines can occur in the elderly as a result of long-term use. Benzodiazepines, along with antihypertensives and drugs affecting the cholinergic system, are the most common cause of drug-induced dementia affecting over 10 percent of patients attending memory clinics. Long-term use of benzodiazepines in the elderly can lead to a pharmacological syndrome with symptoms including drowsiness, ataxia, fatigue, confusion, weakness, dizziness, vertigo, tinnitus, syncope, reversible dementia, depression, impairment of intellect, psychomotor and sexual dysfunction, agitation, auditory and visual hallucinations, paranoid ideation, panic, delirium, depersonalization, sleepwalking, aggression, orthostatic hypotension, and insomnia. Depletion of certain neurotransmitters and cortisol levels and alterations in immune function, biological markers, and endocrine disorders can also occur. Elderly individuals who have been long-term users of benzodiazepines have been found to have a higher incidence of postoperative confusion. Benzodiazepines have been associated with increased body sway in the elderly, which can potentially lead to fatal accidents including falls. Discontinuation of benzodiazepines leads to improvement in the balance of the body and also leads to improvements in cognitive functions in the elderly benzodiazepine hypnotic users without worsening of insomnia.

Withdrawal & Recovery

Given the multiphasic nature of chemically induced toxic neuroinflammation, withdrawing from a benzodiazepine requires analyzing the current neurological state from neuroelectrophysiological, neuroendocrine, circulatory, aging, pro-inflammatory, immune, symptomatic, radio-diagnostic, and neurodegenerative perspectives. Insight into the current state can help estimate withdrawal symptoms to establish an optimal taper plan and decide whether it is the right time to taper. There is no standard taper or counteracting drug to safely withdraw from benzodiazepine dependency. Abrupt withdrawals or dosage reductions will render some symptomatic relief however the associated GABAergic downregulation will also cause excitotoxic rise without neurogenesis in an adult brain. Withdrawals usually lead to a cyclic overstimulation followed by a neuroprotective setback thereby a wavy, never-ending fluctuation in symptoms continues.

Therapeutic support to overcome benzodiazepine dependency or withdrawal symptoms requires strategic interventions to induce circulatory improvements first before viable neurogenesis can occur. Neurogenesis is particularly a challenge to achieve in an adult brain and requires addressing all aspects of brain health before it can accept regenerative components to replace damaged glia and neurons. Currently, unresolvable circulatory obstructions in the brain, necrosis; fibrotic transformations, post-therapeutic lifestyle, and continued chemical interferences present top challenges in recovery. Although an ideal immunomodulatory regenerative therapy rendered to a subject who accurately matches sound inclusion criteria and follows lifestyle discipline post-therapy will exhibit lasting improvements.