Norepinephrine depletion facilitates recovery of function after focal ischemia in the rat

Abstract

Previous studies have suggested that increased norepinephrine plays an important role in recovery of function after brain injury; however, the majority of these studies used drugs that are known to also affect other monoamines to increase or decrease norepinephrine. The purpose of the present study was to determine if norepinephrine is required to promote recovery after ischemia. A form of enriched rehabilitation was used to rehabilitate animals after ischemia and the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine was used to selectively destroy norepinephrine projections from the locus coeruleus. Three sensorimotor tests were used to evaluate the recovery of the animals. Depletion of norepinephrine improved sensorimotor recovery in standard-housed animals and did not impede recovery in the rehabilitation groups. Dopamine beta hydroxylase staining was used to confirm N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine-depleted terminal norepinephrine levels. The amount of norepinephrine terminal staining negatively correlated with recovery of function in the staircase test after ischemia. In addition, enriched rehabilitation increased, but depletion of norepinephrine had no effect on, brain-derived neurotrophic factor protein levels, which have also been linked to improved recovery of function. Together the above findings question the previously postulated role of norepinephrine in recovery of function after stroke.

Depletion of Endogenous Noradrenaline Does Not Prevent Spinal Cord Plasticity Following Peripheral Nerve Injury

“…We and others have shown that peripheral nerve injury increases BDNF content in the primary sensory neurons and the spinal dorsal horn 11, 16, 26, 34 . Previous studies demonstrated that depletion of noradrenaline itself does not alter BDNF content or expression in the brain 18, 40 , consistent with the lack of effect of noradrenaline depletion on glial activity in the brain in the absence of nerve injury 22 . Although the current study did not test whether NA depletion alters BDNF content in the spinal dorsal horn in the absence of injury, these previous observations in the brain suggest that NA depletion itself is unlikely to affect spinal BDNF content.…”

Executive (dys)function after stroke: special considerations for behavioral pharmacology

“…This may be due to a receptor-specific effect as Okada and colleagues (2005) reported that antagonism of the D4 receptor attenuated stroke-induced cell damage in vitro. Finally, while others have shown that reductions in NE were associated with worse functional recovery (Beltran et al, 2010), Windle and colleagues (2007) noted beneficial effects of NE depletion on a variety of rodent tests of motoric ability. These collective findings suggest that the relationship between post-stroke recovery and monoaminergic-system modulation may be more complex than previously appreciated, presenting additional challenges in translating findings from rodents to humans, and implementing these interventions in the clinic.…”

Is Environmental Enrichment Ready for Clinical Application in Human Post-stroke Rehabilitation?

“…The preclinical stroke field has primarily used EE to promote motor recovery and study its underlying neuroplastic mechanisms. Many studies have demonstrated benefits of EE on post-stroke recovery of a variety of sensorimotor tasks (see Table 2 ), including: rotarod (Ohlsson and Johansson, 1995 ; Johansson and Ohlsson, 1996 ; Johansson, 1996 ; Nygren and Wieloch, 2005 ; Nygren et al, 2006 ; Buchhold et al, 2007 ), ladder crossing (Biernaskie et al, 2004 ; Windle et al, 2007 ; Wurm et al, 2007 ), limb placement (Puurunen et al, 2001 ), and adhesive strip removal (Kuptsova et al, 2015 ). While some studies have shown neutral, or slightly negative effects of EE on similar sensorimotor tasks (Hicks et al, 2008 ), meta-analysis of these results indicates that EE has a significant benefit on general sensorimotor function (Janssen et al, 2010 ).…”

“…As only ~17% of EE studies have included both male and female animals, and of this subset only a minority of studies has been concerned with the effects of stroke, or stroke recovery, it is unlikely that enough data currently exists in the literature to definitively answer the conditions under which sex-specific effects of EE may occur (Simpson and Kelly, 2011 ). As previously outlined, EE has shown beneficial effects for both cognitive and motor recovery using a variety of models of neurological damage including: global ischemia (Farrell et al, 2001 ), neonatal hypoxia-ischemia (Pereira et al, 2007 ; Rojas et al, 2013 ), intracerebral hemorrhage (Auriat and Colbourne, 2008 ), and cortical injury in a variety of regions using different lesion induction methods (Kolb and Gibb, 1991 ; Johansson, 2004 ; Buchhold et al, 2007 ; Windle et al, 2007 ; Jeffers et al, 2014 ; Kuptsova et al, 2015 ). Another important consideration is whether the beneficial effects of EE are lasting, since the vast majority of preclinical EE studies maintain enrichment until the time of sacrifice.…”