Neuroprotective Profile of Enoxaparin, a Low Molecular Weight Heparin, in In Vivo Models of Cerebral Ischemia or Traumatic Brain Injury in Rats: a Review

Abstract

The development of treatments for acute neurodegenerative diseases (stroke and brain trauma) has focused on (i) re-establishing blood flow to ischemic areas as quickly as possible (i.e. mainly antithrombotics or thrombolytics for stroke therapy) and (ii) on protecting neurons from cytotoxic events (i.e. neuroprotective therapies such as anti-excitotoxic or anti-inflammatory agents for stroke and neurotrauma therapies). This paper reviews the preclinical data for enoxaparin in in vivo models of ischemia and brain trauma in rats. Following a photothrombotic lesion in the rat, enoxaparin significantly reduced edema at 24 h after lesion when the treatment was started up to 18 h after insult. Enoxaparin was also tested after an ischemic insult using the transient middle cerebral artery occlusion (tMCAO) model in the rat. Enoxaparin, 2´1.5 mg/kg i.v., significantly reduced the lesion size and improved the neuroscore when the treatment was started up to 5 h after ischemia. Enoxaparin, administered at 5h after insult, reduced cortical lesion size in a dose-dependent manner. In permanent MCAO, enoxaparin (5 and 24 h after insult) significantly reduced lesion size and improved neuroscore. A slight and reversible elevation of activated partial thromboplastin time (APTT) suggests that enoxaparin is neuroprotective at a non-hemorrhagic dose. Traumatic brain injury (TBI) is often accompanied by secondary ischemia due in part to edema-induced compression of blood vessels. When enoxaparin, at 0.5 mg/kg i.v. + 4´1 mg/kg s.c., was administered later than 30h after TBI, it significantly reduced edema in hippocampus and parietal cortex. At one week after TBI the lesion size was significantly reduced and the neurological deficit significantly improved in enoxaparin treated animals. Finally, the cognitive impairment was significantly improved by enoxaparin at 48 h to 2 weeks after TBI. The anticoagulant properties of unfractionated heparin and specifically enoxaparin can explain their anti-ischemic effects in experimental models. Furthermore, unfractionated heparin and specifically enoxaparin, have, in addition to anticoagulant, many other pharmacological effects (i.e. reduction of intracellular Ca 2+ release; antioxidant effect; anti-inflammatory or neurotrophic effects) that could act in synergy to explain the neuroprotective activity of enoxaparin in acute neurodegenerative diseases. Finally, we demonstrated, that in different in vivo models of acute neurodegenerative diseases, enoxaparin reduces brain edema and lesion size and improves motor and cognitive functional recovery with a large therapeutic window of opportunity (compatible with a clinical application). Taking into account these experimental data in models of ischemia and brain trauma, the clinical use of enoxaparin in acute neurodegenerative diseases warrants serious consideration.

Disturbed Ca2+signaling and apoptosis of medium spiny neurons in Huntington's disease

“…4 A-D). Intravenous injections of Enoxaparin are neuroprotective in animal models of stroke and neurodegenerative diseases (26)(27)(28), and our results indicate that Enoxaparin may also be worthy of assessment as HD therapeutics. Recently, a number of biologically active Food and Drug Administrationapproved heterocyclic, tricyclic, and phenothiazine-derived compounds have been identified as putative MPTP blockers (21).…”

Inflammation and the neurovascular unit in the setting of focal cerebral ischemia

“…enoxaparin) in rodent models of MCA occlusion, have shown significantly decreased in residual volumes of infarction and improvement in behavioral outcome. (Stutzmann et al, 2002) Early studies in the non-human primate had already shown that heparin (and ticlopidine in combination) could significantly reduce the density of microvessel occlusions in the ischemic territory. Those studies suggest that by limiting coagulation system activation, and blocking the effects of endothelial cell activation, the effects of Virchow’s triad can be reduced.…”

DL-3-n-butylphthalide induced neuroprotection, regenerative repair, functional recovery and psychological benefits following traumatic brain injury in mice

“…Although the initial trigger of the brain damage induced by the mechanical strike in TBI is different from stroke, the pathological signaling pathways and the consequent cell death mechanisms in TBI share some similarities with ischemic strokes, and there is often a second ischemic damage after the initial TBI insult (Bramlett and Dietrich, 2004; Simard et al, 2010; Stutzmann et al, 2002). Specifically, regional ischemia is one of the main events in TBI secondary injury due to the damage to vasculatures (Simard et al, 2010; Stutzmann et al, 2002). It is also well characterized that excitotoxicity and apoptosis are mainly responsible for neuronal damage in both ischemic stroke and TBI (Liou et al, 2003).…”