Targeting the Nervous System
Nathan Keighley in Miraculous Medicines and the Chemistry of Drug Design, 2020
The nervous system is composed of two parts: the central nervous system (CNS; brain and spinal cord) and peripheral nervous system, which extends the entire body. Sensory neurons carry information from the body to the CNS, while motor nerves carry messages from the CNS to the rest of the body. Information from a stimulus is carried to the CNS by the sensory neurones; here, the messages are coordinated and the appropriate messages are then sent from the CNS to effectors, which can be organs or muscles, to generate a response to the stimulus. For example, if a person was to touch a hot object, for example they accidentally touch the ring on a hot cooker, the information from the stimulus, measured by temperature receptors in the skin, travels via a sensory neurone to a coordinator, such as a connector neurone within the CNS, which produces an automatic response to move the hand away from the heat by sending signals down motor neurones to the effector muscles. This pathway of neurones is known as a reflex arc. The response is immediate because only three neurones are involved and it is an automatic, involuntary response because it bypasses the brain to save time and avoid damage.
Issues and controversies involving the peripheral nervous system evaluation
James W. Albers, Stanley Berent in Neurobehavioral Toxicology: Neurological and Neuropsychological Perspectives, 2005
It is important to remember that a 40% decline in the sensory response amplitude is not equivalent to a 40% decline in the pool of sensory neurons or sensory axons. Consider the sural nerve, a purely sensory nerve. The sural sensory response amplitude does not decline linearly from within the normal range to zero as sensory neurons or axons decline from a normal value of about 10,000/mm2 to zero. Instead, a relatively modest decline in the number of neurons or axons results in an unobtainable sural response. In other words, the sensory response amplitude is truncated so that, even after reaching a value of zero, there is still a large range of clinical dysfunction, varying from minor sensory loss to complete loss of sensation. This example is not analogous to the relationship between loss of neurons in the basal ganglia and the onset of parkinsonism. In fact, loss of a very small percentage of sensory neurons or axons results in sensory symptoms, electrophysiologic abnormalities, and evidence of sensory signs.
Neurosciences and diseases of the mind
R. Paul Thompson, Ross E.G. Upshur in Philosophy of Medicine, 2017
This increased focus on the brain has led to a number of new models. One of particular philosophical interest is the connectionist model. This model views the brain as a network of neural pathways. Any model of the brain has to explain input, processing, outputs and memory (learning). The first three are explained by the web of neurons (see Figure 11.1). Some neurons are sensory neurons. These are input neurons. Others – a vast web of them – are processing neurons. These constitute the inner workings of the brain. The third kind of neuron is output neurons. These, for example, innervate muscles. The processing neurons give rise to inner sensations: thoughts, desires, consciousness, a sense of self and so on.
C. elegans: a sensible model for sensory biology
Published in Journal of Neurogenetics, 2020
Sensory neurobiology exists at the interface between biology, chemistry and physics. Our sensory processes mediate our interaction with the physical world. It is incredible that life has evolved to detect a vast array of forces and molecules present in our universe. Organisms as seemingly disparate as nematodes and humans have much in common in regard to their sensory processes. The relationship of an organism with its external and internal environments arguably begins with the sensory inputs and ends with behavioral output. Perception occurs via sensory neurons that activate in response to specific stimuli. These cues act upon sensory transduction machinery expressed by the sensory neuron itself or in specialized structures that communicate with the sensory neuron. Some of these sensory structures have evolved into large complex organs, such as the mammalian eye. However, such complexity incorporating large numbers of cells is not required for a sophisticated sensory system. Even a tiny one millimeter long organism with a compact nervous system of only 302 neurons can detect a surprisingly vast and varied array of physical stimuli, such as mechanical forces, chemicals, light, temperature, humidity and electromagnetic fields (Figure 1). The evolution of these sensory modalities confers numerous benefits to survival, including the ability to find food and mates and to avoid hazard.
Using Xenopus oocytes in neurological disease drug discovery
Published in Expert Opinion on Drug Discovery, 2020
Steven L. Zeng, Leland C. Sudlow, Mikhail Y. Berezin
In addition, a new type of pain caused by common by chemotherapy drugs leads to the condition known as chemotherapy induced peripheral neuropathy (CIPN). CIPN occurs in nearly 10 – 60% of patients treated with first-line chemotherapy drugs. Patients with acute neurotoxicity appear to be at increased risk for chronic neuropathy in which painful symptoms persist long after cessation of chemotherapy. Deterioration of sensory neurons and their axons leads to the loss of nerve fibre density and nociception, and this also puts the patient at greater risk of serious damage to the hands or feet. CIPN can be debilitating and is frequently the primary reason for patients choosing to discontinue chemotherapy. To date, most of the CIPN prevention trials have not demonstrated benefits compared to treatment with a placebo, and therefore novel targets are critically needed. A number of recent studies used Xenopus oocytes to test new targets and identify new active drug candidates. Thus, Romero et al. developed a novel peptide RgIA4 that exhibits high potency for both human and rodent α9α10 nAChR [116], a recently discovered ion channel that has been implicated in the neuropathic pain, including CIPN [117].
Transient receptor potential ankyrin 1 (TRPA1)-mediated toxicity: friend or foe?
Published in Toxicology Mechanisms and Methods, 2020
Mohaddeseh Sadat Alavi, Ali Shamsizadeh, Gholamreza Karimi, Ali Roohbakhsh
Chemotherapy-induced peripheral neuropathy (CIPN), as a common side effect of many anti-cancer drugs such as vinca alkaloids, is associated with the severe pain syndrome that compromises treatment in many patients (Quasthoff and Hartung 2002). At present, there is no effective treatment for this syndrome (Quasthoff and Hartung 2002). TRP channels are expressed in the sensory neurons (Patapoutian et al. 2009). Recent studies suggest that TRP channels are liable for chemotherapy-induced peripheral neuropathies (Ta et al. 2010; Descoeur et al. 2011). It was demonstrated that vinca alkaloids (vinblastine and vincristine) exposure caused an immediate pain syndrome in both flies and mice. This effect was mediated by production of an inward sodium current resulting in neuronal firing and excitation of sensory neurons (Boiko et al. 2017). These neuronal abnormalities, following vinca alkaloids treatment, required TRPA1 channel activation. Furthermore, the vinca alkaloids-induced painful stimuli were decreased in TRPA1 mutant flies and mice. The findings revealed that TRPA1 is an important target for the development of vinca alkaloids-induced peripheral neuropathy (Boiko et al. 2017).
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