Spinal Astrocyte Glutamate Receptor 1 Overexpression after Ischemic Insult Facilitates Behavioral Signs of Spasticity and Rigidity

Hefferan, Michael P.; Kuchárová, Karolı́na; Kinjo, Kiyohiko; Kakinohana, Osamu; Sekerková, Gabriella; Nakamura, Seiya; Fuchigami, Tatsuya; Tomori, Z; Yaksh, Tony L.; Kurtz, Neil M.; Maršala, Martin

doi:10.1523/jneurosci.0989-07.2007

Cited by 37 publications

(35 citation statements)

References 54 publications

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“…Accordingly, dorsal rhizotomy provides a potent and long lasting anti-spasticity effect in both human patients and animal models of experimental spasticity. We have recently demonstrated a potent anti-spasticity effect after systemic or intrathecal treatment with AMPA receptor antagonist NXG424 (Hefferan et al, 2007, Oshiro et al, 2010). Thus a potent anti-spasticity effect seen in our current tizanidine study can in part result from suppression of excitatory amino acid (glutamate) release from primary afferents and excitatory interneurons.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we have demonstrated a comparable AMPA-evoked glutamate release in cultured astrocytes which was effectively blocked by the AMPA receptor antagonist NGX424 (Hefferan et al, 2007). In our current study, a significant upregulation of α2A receptor in activated astrocytes in animals with ischemic spasticity was seen.…”

Section: Discussionmentioning

confidence: 99%

“…Using this model we have demonstrated i) a selective loss of spinal GABA-ergic interneurons but persisting survival of α-motoneurons after 10 min of transient spinal cord ischemia (Taira and Marsala, 1996), ii) a significant increase in myogenic motor evoked potentials and Hoffmann reflex activity (Marsala et al, 2004, Kakinohana et al, 2006), iii) progressive appearance of spasticity and rigidity as measured by a computer-controlled ankle rotational muscle resistance meter (Marsala et al, 2005), and iv) effective suppression of spasticity, rigidity and H-reflex activity by spinal delivery of GABA-mimetic compounds such as nipecotic acid, GABA B receptor agonist baclofen and AMPA receptor antagonist NGX424 (Kakinohana et al, 2006, Hefferan et al, 2007). In addition, using the same spinal ischemia model, we have characterized in spastic animals the development of baclofen tolerance after chronic intrathecal infusion of baclofen (Hefferan et al, 2006) and have demonstrated effective suppression of spasticity in baclofen-tolerant animals after intrathecal or systemic treatment with AMPA receptor antagonist NGX424 (Oshiro et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Potent suppression of stretch reflex activity after systemic or spinal delivery of tizanidine in rats with spinal ischemia-induced chronic spastic paraplegia

et al. 2011

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Background Spasticity and rigidity are serious complications associated with spinal traumatic or ischemic injury. Clinical studies show that Tizanidine (Tiz) is an effective anti-spasticity agent, however, the mechanism of this effect is still not clear. Tiz binds not only to α2-adrenoreceptors (AR) but also to imidazoline (I) receptors. Both receptor systems (AR+I) are present in the spinal cord interneurons and α-motoneurons. The aim of the present study was to evaluate the therapeutic potency of systematically or spinally (intrathecally) delivered Tiz on stretch reflex activity (SRA) in animals with ischemic spasticity, and to delineate supraspinal or spinal sites of Tiz action. Methods Animals were exposed to 10 min of spinal ischemia to induce an increase in SRA. Increase in SRA was identified by simultaneous increase in recorded EMG activity and ankle resistance measured during computer-controlled ankle dorsiflexion (40°/3 sec) in fully awake animals. Animals with increased SRA were divided into several experimental subgroups and treated as follows: i) Tiz administered systemically at the dose of 1 mg kg-1, or intrathecally (IT) at 10 μg or 50 μg delivered as a single dose; ii) Treatment with systemic Tiz was followed by the systemic injection of vehicle, or by non-selective AR antagonist without affinity for imidazoline receptors; Yohimbine (Yoh), α2A AR antagonist; BRL44408 (BRL), α2B AR antagonist; ARC239 (ARC), non-selective AR and I1 receptor antagonist; Efaroxan (Efa), or non-selective AR and I2 receptor antagonist; Idazoxan (Ida); iii) Treatment with IT Tiz was followed by the IT injection of selective α2A AR antagonist; Atipamezole (Ati). In a separate group of spastic animals the effect of systemic Tiz treatment (1 mg/kg) or isoflurane anesthesia on H-reflex activity was also studied. Results Systemic and/or IT treatment with Tiz significantly suppressed SRA. This Tiz-mediated anti-SRA effect was reversed by BRL (5 mg kg-1), Efa (1 mg kg-1) and Ida (1 mg kg-1). No reversal was seen after Yoh (3 mg kg-1) or ARC (5 mg kg-1) treatment. Anti-SRA induced by IT Tiz (50 μg) was reversed by IT injection of Ati (50 μg). Significant suppression of H-reflex was measured after systemic Tiz treatment (1mg/kg) or isoflurane (2%) anesthesia, respectively. Immunofluoresecene staining of spinal cord sections taken from animals with spasticity showed upregulation of α-2A receptor in activated astrocytes. Conclusions These data suggest that α2A AR and I receptors, but not α2B AR primarily mediate the Tiz-induced anti-spasticity effect. This effect involves spinal and potentially supraspinal sites and likely targets α2A receptor present on spinal neurons, primary afferents and activated astrocytes Further studies using highly selective antagonists are needed to elucidate the involvement of specific subtypes of the AR and imidazoline receptors in the anti-spasticity effect seen after Tiz treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Potent suppression of stretch reflex activity after systemic or spinal delivery of tizanidine in rats with spinal ischemia-induced chronic spastic paraplegia

et al. 2011

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“…The Hoffman (H) reflex was recorded as previously described [23, 41]. Briefly, under isoflurane anesthesia, the left hindlimb of the animal was secured and a transcutaneous stimulating needle electrode inserted adjacent to the tibial nerve at the ankle.…”

Section: Methodsmentioning

confidence: 99%

Allodynia and hyperalgesia in diabetic rats are mediated by GABA and depletion of spinal potassium-chloride co-transporters

Jolivalt¹,

Lee²,

Ramos³

et al. 2008

Pain

135

149

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Diabetic rats show behavioral indices of painful neuropathy that may model the human condition. Hyperalgesia during the formalin test in diabetic rats is accompanied by the apparently paradoxical decrease in spinal release of excitatory neurotransmitters and increase in the inhibitory neurotransmitter GABA. Decreased expression of the potassium-chloride co-transporter, KCC2, in the spinal cord promotes excitatory properties of GABA. We therefore measured spinal KCC2 expression and explored the role of the GABAA receptor in rats with painful diabetic neuropathy. KCC2 protein levels were significantly reduced in the spinal cord of diabetic rats while levels of NKCC1 and the GABAA receptor were unchanged. Spinal delivery of the GABAA receptor antagonist bicuculline reduced formalin-evoked flinching in diabetic rats and also dose-dependently alleviated tactile allodynia. GABAA receptor-mediated rate-dependent depression of the spinal H reflex was absent in the spinal cord of diabetic rats. Control rats treated with the KCC2 blocker DIOA, mimicked diabetes by showing increased formalin-evoked flinching and diminished rate dependent depression. The ability of bicuculline to alleviate allodynia and formalin-evoked hyperalgesia in diabetic rats is consistent with a reversal of the properties of GABA predicted by reduced spinal KCC2 and suggests that reduced KCC2 expression and increased GABA release contribute to spinally-mediated hyperalgesia in diabetes.

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“…Spinal cord ischemia was induced in anesthesized male Sprague Dawley rats according to a previously described protocol (Taira and Marsala, 1996; Hefferan et al, 2007). This protocol involves inflating a balloon catheter placed in the descending thoracic aorta at the level of the left subclavian artery to occlude aortic blood flow for 10 min while also maintaining systemic hypotension.…”

Section: Methodsmentioning

confidence: 99%

The Rheb–mTOR Pathway Is Upregulated in Reactive Astrocytes of the Injured Spinal Cord

Codeluppi¹,

Svensson²,

Hefferan³

et al. 2009

J. Neurosci.

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140

109

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Astrocytes in the CNS respond to tissue damage by becoming reactive. They migrate, undergo hypertrophy, and form a glial scar that inhibits axon regeneration. Therefore, limiting astrocytic responses represents a potential therapeutic strategy to improve functional recovery. It was recently shown that the epidermal growth factor (EGF) receptor is upregulated in astrocytes after injury and promotes their transformation into reactive astrocytes. Furthermore, EGF receptor inhibitors were shown to enhance axon regeneration in the injured optic nerve and promote recovery after spinal cord injury. However, the signaling pathways involved were not elucidated. Here we show that in cultures of adult spinal cord astrocytes EGF activates the mTOR pathway, a key regulator of astrocyte physiology. This occurs through Akt-mediated phosphorylation of the GTPase-activating protein Tuberin, which inhibits Tuberin's ability to inactivate the small GTPase Rheb. Indeed, we found that Rheb is required for EGF-dependent mTOR activation in spinal cord astrocytes, whereas the Ras-MAP kinase pathway does not appear to be involved. Moreover, astrocyte growth and EGF-dependent chemoattraction were inhibited by the mTOR-selective drug rapamycin. We also detected elevated levels of activated EGF receptor and mTOR signaling in reactive astrocytes in vivo in an ischemic model of spinal cord injury. Furthermore, increased Rheb expression likely contributes to mTOR activation in the injured spinal cord. Interestingly, injured rats treated with rapamycin showed reduced signs of reactive gliosis, suggesting that rapamycin could be used to harness astrocytic responses in the damaged nervous system to promote an environment more permissive to axon regeneration.

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Spinal Astrocyte Glutamate Receptor 1 Overexpression after Ischemic Insult Facilitates Behavioral Signs of Spasticity and Rigidity

Cited by 37 publications

References 54 publications

Potent suppression of stretch reflex activity after systemic or spinal delivery of tizanidine in rats with spinal ischemia-induced chronic spastic paraplegia

Potent suppression of stretch reflex activity after systemic or spinal delivery of tizanidine in rats with spinal ischemia-induced chronic spastic paraplegia

Allodynia and hyperalgesia in diabetic rats are mediated by GABA and depletion of spinal potassium-chloride co-transporters

The Rheb–mTOR Pathway Is Upregulated in Reactive Astrocytes of the Injured Spinal Cord

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