Int J Neurosci. 2006 Jul;116(7):775-826.

Serotonergic mechanisms in amyotrophic lateral sclerosis.

Sandyk R.

The Carrick Institute for Clinical Ergonomics Rehabilitation, and Applied Neurosciences, School of Engineering Technologies State University of New York at Farmingdale, Farmingdale, New York 11735, USA. rsandyk@optonline.net

Serotonin (5-HT) has been intimately linked with global regulation of motor behavior, local control of motoneuron excitability, functional recovery of spinal motoneurons as well as neuronal maturation and aging. Selective degeneration of motoneurons is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Motoneurons that are preferentially affected in ALS are also densely innervated by 5-HT neurons (e.g., trigeminal, facial, ambiguus, and hypoglossal brainstem nuclei as well as ventral horn and motor cortex). Conversely, motoneuron groups that appear more resistant to the process of neurodegeneration in ALS (e.g., oculomotor, trochlear, and abducens nuclei) as well as the cerebellum receive only sparse 5-HT input. The glutamate excitotoxicity theory maintains that in ALS degeneration of motoneurons is caused by excessive glutamate neurotransmission, which is neurotoxic. Because of its facilitatory effects on glutaminergic motoneuron excitation, 5-HT may be pivotal to the pathogenesis and therapy of ALS. 5-HT levels as well as the concentrations 5-hydroxyindole acetic acid (5-HIAA), the major metabolite of 5-HT, are reduced in postmortem spinal cord tissue of ALS patients indicating decreased 5-HT release. Furthermore, cerebrospinal fluid levels of tryptophan, a precursor of 5-HT, are decreased in patients with ALS and plasma concentrations of tryptophan are also decreased with the lowest levels found in the most severely affected patients. In ALS progressive degeneration of 5-HT neurons would result in a compensatory increase in glutamate excitation of motoneurons. Additionally, because 5-HT, acting through presynaptic 5-HT1B receptors, inhibits glutamatergic synaptic transmission, lowered 5-HT activity would lead to increased synaptic glutamate release. Furthermore, 5-HT is a precursor of melatonin, which inhibits glutamate release and glutamate-induced neurotoxicity. Thus, progressive degeneration of 5-HT neurons affecting motoneuron activity constitutes the prime mover of the disease and its progression and treatment of ALS needs to be focused primarily on boosting 5-HT functions (e.g., pharmacologically via its precursors, reuptake inhibitors, selective 5-HT1A receptor agonists/5-HT2 receptor antagonists, and electrically through transcranial administration of AC pulsed picotesla electromagnetic fields) to prevent excessive glutamate activity in the motoneurons. In fact, 5HT1A and 5HT2 receptor agonists have been shown to prevent glutamate-induced neurotoxicity in primary cortical cell cultures and the 5-HT precursor 5-hydroxytryptophan (5-HTP) improved locomotor function and survival of transgenic SOD1 G93A mice, an animal model of ALS.

Neuroreport. 2004 Mar 22;15(4):717-20.

Transcranial magnetic stimulation and BDNF plasma levels in amyotrophic lateral sclerosis.

Angelucci F, Oliviero A, Pilato F, Saturno E, Dileone M, Versace V, Musumeci G, Batocchi AP, Tonali PA, Di Lazzaro V.

Institute of Neurology, Catholic University, Largo Gemelli 8, 00168 Rome, Italy.

Abstract

Low- and high-frequency repetitive transcranial magnetic stimulation (rTMS) of the motor cortex results in lasting changes of excitatory neurotransmission. We investigated the effects of suprathreshold 1 Hz rTMS on brain derived neurotrophic factor (BDNF) plasma levels in 10 healthy subjects and effects of either 1 Hz or 20 Hz rTMS in four amyotrophic lateral sclerosis (ALS) patients. BDNF levels were progressively decreased by 1 Hz rTMS in healthy subjects; there was no effect of 1 Hz rTMS on BDNF plasma levels in ALS patients, an effect probably due to the loss of motor cortex pyramidal cells. High frequency rTMS determined a transitory decrease in BDNF plasma levels. Cumulatively these findings suggest that rTMS might influence the BDNF production by interfering with neuronal activity.

Curr Opin Neurol. 2000 Aug;13(4):397-405.

Recent advances in amyotrophic lateral sclerosis.

Al-Chalabi A, Leigh PN.

Department of Neurology, Guy’s King’s and St Thomas’ School of Medicine and Institute of Psychiatry, De Crespigny Park, London, UK.

The mechanisms by which mutations of the SOD1 gene cause selective motor neuron death remain uncertain, although interest continues to focus on the role of peroxynitrite, altered peroxidase activity of mutant SOD1, changes in intracellular copper homeostasis, protein aggregation, and changes in the function of glutamate transporters leading to excitotoxicity. Neurofilaments and peripherin appear to play some part in motor neuron degeneration, and amyotrophic lateral sclerosis is occasionally associated with mutations of the neurofilament heavy chain gene. Linkage to several chromosomal loci has been established for other forms of familial amyotrophic lateral sclerosis, but no new genes have been identified. In the clinical field, interest has been shown in the population incidence and prevalence of amyotrophic lateral sclerosis and the clinical variants that cause diagnostic confusion. Transcranial magnetic stimulation has been used to detect upper motor neuron damage and to explore cortical excitability in amyotrophic lateral sclerosis, and magnetic resonance imaging including proton magnetic resonance spectroscopy and diffusion weighted imaging also provide useful information on the upper motor neuron lesion. Aspects of care including assisted ventilation, nutrition, and patient autonomy are addressed, and underlying these themes is the requirement to measure quality of life with a new disease-specific instrument. Progress has been made in developing practice parameters. Riluzole remains the only drug to slow disease progression, although interventions such as non-invasive ventilation and gastrostomy also extend survival.

Acupunct Electrother Res. 1992;17(2):107-48.

Common factors contributing to intractable pain and medical problems with insufficient drug uptake in areas to be treated, and their pathogenesis and treatment: Part I. Combined use of medication with acupuncture, (+) Qi gong energy-stored material, soft laser or electrical stimulation.

Omura Y, Losco BM, Omura AK, Takeshige C, Hisamitsu T, Shimotsuura Y, Yamamoto S, Ishikawa H, Muteki T, Nakajima H, et al.

Heart Disease Research Foundation, New York.

Most frequently encountered causes of intractable pain and intractable medical problems, including headache, post-herpetic neuralgia, tinnitus with hearing difficulty, brachial essential hypertension, cephalic hypertension and hypotension, arrhythmia, stroke, osteo-arthritis, Minamata disease, Alzheimer’s disease and neuromuscular problems, such as Amyotrophic Lateral Sclerosis, and cancer are often found to be due to co-existence of 1) viral or bacterial infection, 2) localized microcirculatory disturbances, 3) localized deposits of heavy metals, such as lead or mercury, in affected areas of the body, 4) with or without additional harmful environmental electro-magnetic or electric fields from household electrical devices in close vicinity, which create microcirculatory disturbances and reduced acetylcholine. The main reason why medications known to be effective prove ineffective with intractable medical problems, the authors found, is that even effective medications often cannot reach these affected areas in sufficient therapeutic doses, even though the medications can reach the normal parts of the body and result in side effects when doses are excessive. These conditions are often difficult to treat or may be considered incurable in both Western and Oriental medicine. As solutions to these problems, the authors found some of the following methods can improve circulation and selectively enhance drug uptake: 1) Acupuncture, 2) Low pulse repetition rate electrical stimulation (1-2 pulses/second), 3) (+) Qi Gong energy, 4) Soft lasers using Ga-As diode laser or He-Ne gas laser, 5) Certain electro-magnetic fields or rapidly changing or moving electric or magnetic fields, 6) Heat or moxibustion, 7) Individually selected Calcium Channel Blockers, 8) Individually selected Oriental herb medicines known to reduce or eliminate circulatory disturbances. Each method has advantages and limitations and therefore the individually optimal method has to be selected. Applications of (+) Qi Gong energy stored paper or cloth every 4 hours, along with effective medications, were often found to be effective, as Qigongnized materials can often be used repeatedly, as long as they are not exposed to rapidly changing electric, magnetic or electro-magnetic fields. Application of (+) Qi Gong energy-stored paper or cloth, soft laser or changing electric field for 30-60 seconds on the area above the medulla oblongata, vertebral arteries or endocrine representation area at the tail of pancreas reduced or eliminated microcirculatory disturbances and enhanced drug uptake.(ABSTRACT TRUNCATED AT 400 WORDS)