A Selective Phosphodiesterase-4 Inhibitor Reduces Leukocyte Infiltration, Oxidative Processes, and Tissue Damage after Spinal Cord Injury

Abstract

We tested the hypothesis that a selective phosphodiesterase type 4 inhibitor (PDE4-I; IC486051) would attenuate early inflammatory and oxidative processes following spinal cord injury (SCI) when delivered during the first 3 days after injury. Rats receiving a moderately severe thoracic-clip-compression SCI were treated with the PDE4-I (0.5, 1.0, and 3.0 mg/kg IV) in bolus doses from 2-60 h post-injury. Doses at 0.5 mg/kg and 1.0 mg/kg significantly decreased myeloperoxidase (MPO) enzymatic activity (neutrophils), expression of a neutrophil-associated protein and of ED-1 (macrophages), and estimates of lipid peroxidation in cord lesion homogenates at 24 h and 72 h post-injury by 25-40%. The 3.0 mg/kg dose had small or no effects on these measures. The PDE4-I treatment (0.5 or 1.0 mg/kg) reduced expression of the oxidative enzymes gp91 phox , inducible nitric oxide synthase, and cyclooxygenase-2, and diminished free radical generation by up to 40%. Treatment with 0.5 mg/kg PDE4-I improved motor function (as assessed by the Basso-Beattie-Bresnahan scale) significantly from 4-8 weeks after SCI (average difference 1.3 points). Mechanical allodynia elicited from the hindpaw decreased by up to 25%. The PDE4-I treatment also increased white matter volume near the lesion at 8 weeks after SCI. In conclusion, the PDE4-I reduced key markers of oxidative stress and leukocyte infiltration, producing cellular protection, locomotor improvements, and a reduction in neuropathic pain. Early inhibition of PDE4 is neuroprotective after SCI when given acutely and briefly at sufficient doses.

Systemic Administration of Propentofylline, Ibudilast, and (+)-Naltrexone Each Reverses Mechanical Allodynia in a Novel Rat Model of Central Neuropathic Pain

“…59 Further, selective PDE4 inhibitors decrease hindpaw allodynia from compression SCI by reducing immune cell infiltration/activation and free radical formation. 5 PPF is a methyl-xanthine selective PDE4 inhibitor, 72 an isoform expressed in both microglia and astrocytes. 51 Although neurons express PDE4, PDE4 is the major isoform expressed in immune and inflammatory cells.…”

Proinflammatory cytokine regulation of cyclic AMP‐phosphodiesterase 4 signaling in microglia in vitro and following CNS injury

“…This would imply that PDE4, which accounts for the majority of PDE activity in the CNS (Kleppisch, 2009), is the predominant PDE in immune cells (macrophages, eosinophils, neutrophils and microglia) (Semmler et al, 1993; Ghosh and Pearse, 2010) and has been identified in the injured spinal cord (Whitaker et al, 2008), could be regulated by pro-inflammatory cytokines such as TNF-α and IL-1β to decrease cyclic AMP. Rolipram, and other PDE4 inhibitors, in addition to preventing injury-induced decreases in cyclic AMP, also have potent anti-inflammatory actions (Bao et al, 2011; Atkins et al, 2007; Pearse et al, 2004b). Collectively this work implies that cyclic AMP dysregulation after CNS injury may be central to microglia activation and their ensuing auto-activation through pro-inflammatory cytokine production.…”

Sensory function after cavernous haemangioma: a case report of thermal hypersensitivity at and below an incomplete spinal cord injury

“…24,25 Analysis of specific pain symptoms and signs related to IH in this case study also indirectly suggests a role for neuroinflammation in the development of local and remote cold allodynia. Acute cerebrospinal fluid levels of the inflammatory cytokine tumour necrosis factor-a has been correlated with NP shortly after SCI, 26 specifically with perception of 'sharp' pain, which is similar to the sensation described by our patient during the first month.…”