Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl-l-carnitine: Effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells

Abstract

Prophylactic treatment with acetyl-L-carnitine (ALCAR) prevents the neuropathic pain syndrome that is evoked by the chemotherapeutic agent, paclitaxel. The paclitaxel-evoked pain syndrome is associated with degeneration of the intraepidermal terminal arbors of primary afferent neurons, with the activation of cutaneous Langerhans cells, and with an increased incidence of swollen and vacuolated axonal mitochondria in A-fibers and C-fibers. Previous work suggests that ALCAR is neuroprotective in other nerve injury models and that it improves mitochondrial dysfunction. Thus, we examined whether the prophylactic efficacy of ALCAR was associated with the prevention of intraepidermal terminal arbor degeneration, the inhibition of Langerhans cell activation, or the inhibition of swelling and vacuolation of axonal mitochondria. In animals with a confirmed ALCAR effect, we found no evidence of a neuroprotective effect on the paclitaxel-evoked degeneration of sensory terminal arbors or an inhibition of the paclitaxel-evoked activation of Langerhans cells. However, ALCAR treatment completely prevented the paclitaxel-evoked increase in the incidence of swollen and vacuolated C-fiber mitochondria, while having no effect on the paclitaxel-evoked changes in A-fiber mitochondria. Our results suggest that the efficacy of prophylactic ALCAR treatment against the paclitaxel-evoked pain may be related to a protective effect on C-fiber mitochondria.

The Possible Role of Propolis in Ameliorating Paclitaxel-Induced Peripheral Neuropathy in Sciatic Nerve of Adult Male Albino Rats

“…Our study revealed swollen disrupted mitochondria in the affected myleinated axons, which coincides with many investigators who suggested that mitochondrial swelling is a characteristic sign in paclitaxel axonopathy [37,38] . This could be explained by affection of Mitochondrial permeability transition pore (mPTP) which is a high conductance channel in mitochondrial inner membrane that contains different proteins including adenine nucleotide translocator (ANT), mitochondrial phosphate carrier (PiC), voltage-dependent anion channel (VDAC), and cyclophilin-D (Cyp-D).…”

Peripheral Neuropathy in Ovarian Cancer

“…It was also confirmed that acetyl-L-carnitine does not affect the cytotoxicity of paclitaxel or carboplatin on ovarian cancer cells (Engle et al, 2009). In rats, acetyl-L-carnitine prevented paclitaxel-induced neuropathic pain, the swollen and vacuolated mitochondria caused by paclitaxel in C-fibers, but not in A-fibers (Jin et al, 2008). In addition, acetyl-L-carnitine decreased the spontaneous discharge of A-fibers and C-fibers, and blocked the development of the paclitaxel-evoked pain in the sural nerve of rats .…”

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

“…Moreover, paclitaxel appears to gate the multi-molecular complex containing the voltagedependent anion channel, defined as mitochondrial permeability transition pore (mPTP) [19], thus causing a toxic calcium release from the mitochondria [20]. In accordance with this observation, calcium chelating agents are able to reverse paclitaxel-evoked pain [21], and acetyl-l-carnitine, which prevents mPTP opening [22], reduces the development of paclitaxel-induced neuropathic pain [23]. Administration of bortezomib leads to intracytoplasmatic vacuolization in dorsal root ganglia (DRG) satellite cells, probably due to mitochondrial and endoplasmic reticulum enlargement [24].…”