Mitotoxicity in distal symmetrical sensory peripheral neuropathies

Abstract

Chronic distal symmetrical sensory peripheral neuropathy is a common neurological complication of cancer chemotherapy, HIV treatment and diabetes. Although aetiology-specific differences in presentation are evident, the clinical signs and symptoms of these neuropathies are clearly similar. Data from animal models of neuropathic pain suggest that the similarities have a common cause: mitochondrial dysfunction in primary afferent sensory neurons. Mitochondrial dysfunction is caused by mitotoxic effects of cancer chemotherapeutic drugs of several chemical classes, HIV-associated viral proteins, and nucleoside reverse transcriptase inhibitor treatment, as well as the (possibly both direct and indirect) effects of excess glucose. The mitochondrial injury results in a chronic neuronal energy deficit, which gives rise to spontaneous nerve impulses and a compartmental neuronal degeneration that is first apparent in the terminal receptor arbor—that is, intraepidermal nerve fibres—of cutaneous afferent neurons. Preliminary data suggest that drugs that prevent mitochondrial injury or improve mitochondrial function could be useful in the treatment of these conditions.

Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

“…Although the manifestations of peripheral neuropathy can vary between patients with any of the diseases modeled in our studies, there is a growing appreciation that mitochondrial dysfunction contributes to many types of neuropathy by promoting retraction or loss of peripheral sensory terminals and sensory loss (2)(3)(4). Sensory neurons exhibit a condensed mitochondrial network, and this is particularly apparent in unmyelinated neurons that require very high rates of ATP production to maintain electrical activity along the whole length of the axon due to the absence of nodes of Ranvier to mediate saltatory conduction (8,34).…”

“…Distal dying-back or degeneration of nerve fibers is observed in many axonopathic diseases, including diabetic neuropathy, chemotherapy-induced peripheral neuropathy (CIPN), Friedreich ataxia, Charcot-Marie-Tooth disease type 2, and HIV-associated distal-symmetric neuropathy. There are no therapies for any of these diseases, all of which display some degree of mitochondrial dysfunction (2)(3)(4). This is pertinent, as the growth-cone motility required to maintain fields of innervation consumes 50% of ATP supplies in neurons due to high rates of actin treadmilling (5).…”

Monitoring adverse drug reactions in patients on TDF+3TC+EFV in a tertiary care hospital in Eastern India: a prospective observational study

“…Peripheral neuropathy and tremors were noted in our set up. 20 The introduction of HAART regimens, by preventing opportunistic infections and reducing the incidence of myocarditis, has reduced the prevalence of HIV-associated cardiomyopathy of about 30% and the prevalence of cardiac involvement of AIDS-associated malignancies of about 50%. However, HAART regimens, especially those including protease inhibitors have been shown to cause, in a high proportion of HIV-infected patients, a metabolic syndrome (lipodystrophy/lipoatrophy, dyslipidemia, type 2 diabetes mellitus, insulin resistance) that may be associated with an increased risk of cardiovascular disease (approximately 1.4 cardiac events per 1000 years of therapy according to the Framingham score).…”

50 years forward: mechanisms of hyperglycaemia-driven diabetic complications

“…The realisation that failure of mitochondrial energy production and reduction in mitochondrial density via reduced biogenesis or increased autophagy occurs in many tissues affected by diabetic complications, has led to the investigation of many agents that may support mitochondrial function [16]. However, drugs that specifically target mitochondria have been difficult to develop, although promising preclinical data using such agents as MitoQ and Bendavia have recently been published ( Table 1).…”

“…This leads to inefficient oxidative phosphorylation, resulting in loss of mitochondrial membrane potential and reduced ATP production, as well as an increased tendency towards ROS production. Failure of mitochondrial energy production has been demonstrated in cardiomyopathy, nephropathy and neuropathy [16]. This is thought to lead to increased selective mitochondrial autophagy, resulting in decreased mitochondrial density, failure of energy-dependent cellular functions and activation of cell death pathways.…”