Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion

Abstract

Cao Z, Balasubramanian A, Marrelli SP. Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 minutes after reperfusion. Am J Physiol Regul Integr Comp Physiol 306: R149-R156, 2014. First published December 4, 2013; doi:10.1152/ajpregu.00329.2013.-Traditional methods of therapeutic hypothermia show promise for neuroprotection against cerebral ischemia-reperfusion (I/R), however, with limitations. We examined effectiveness and specificity of pharmacological hypothermia (PH) by transient receptor potential vanilloid 1 (TRPV1) channel agonism in the treatment of focal cerebral I/R. Core temperature (Tcore) was measured after subcutaneous infusion of TRPV1 agonist dihydrocapsaicin (DHC) in conscious C57BL/6 WT and TRPV1 knockout (KO) mice. Acute measurements of heart rate (HR), mean arterial pressure (MAP), and cerebral perfusion were measured before and after DHC treatment. Focal cerebral I/R (1 h ischemia ϩ 24 h reperfusion) was induced by distal middle cerebral artery occlusion. Hypothermia (Ͼ8 h) was initiated 90 min after start of reperfusion by DHC infusion (osmotic pump). Neurofunction (behavioral testing) and infarct volume (TTC staining) were measured at 24 h. DHC (1.25 mg/kg) produced a stable drop in Tcore (33°C) in naive and I/R mouse models but not in TRPV1 KO mice. DHC (1.25 mg/kg) had no measurable effect on HR and cerebral perfusion but produced a slight transient drop in MAP (Ͻ6 mmHg). In stroke mice, DHC infusion produced hypothermia, decreased infarct volume by 87%, and improved neurofunctional score. The hypothermic and neuroprotective effects of DHC were absent in TRPV1 KO mice or mice maintained normothermic with heat support. PH via TRPV1 agonist appears to be a well-tolerated and effective method for promoting mild hypothermia in the conscious mouse. Furthermore, TRPV1 agonism produces effective hypothermia in I/R mice and significantly improves outcome when initiated 90 min after start of reperfusion. cerebral ischemia-reperfusion; hypothermia; neuroprotection; TRPV1 STROKE is the second highest cause of death in the world and the main cause of long-term disability in the United States (43). However, current treatment options for stroke are quite limited (51). Thrombolysis is the only approved method for stroke therapy (41), but it can be applied to less than 10% of the patients due to the stringent treatment criteria (26) and in some cases may even produce further reperfusion injury (2). Mild hypothermia (32-34°C) has been demonstrated to reduce stroke injury and improve neurofunctional recovery in animal studies and has shown promise in small-scale clinical trials (20,25,37,49,50). At present, most clinical therapeutic hypothermia (TH) protocols involve methods of forced cooling such as with cold blankets and ice baths or intravenous methods of cooling (25). Although TH seems to have significant promise in stroke therapy, current protocols are accompanied by many adverse complications, which reduce effectiveness...

Pharmacological hypothermia: a potential for future stroke therapy?

“…77 DHC has been shown to be a specific and effective neuroprotective agent in inducing systemic hypothermia of 33.0 ± 0.2 °C after 100 min in a rodent stroke model. 78 Application of DHC (1.25 mg/kg) did not lead to similar reported cardiovascular depressive effects as capsaicin, with only a slight transient hypotension. 78 In rats given DHC via continuous IV infusion (at 1.0 mg/kg/hr for 5 total hours), there was reportedly increased susceptibility to hypotension and bradycardia in a cardiac arrest model.…”

“…78 Application of DHC (1.25 mg/kg) did not lead to similar reported cardiovascular depressive effects as capsaicin, with only a slight transient hypotension. 78 In rats given DHC via continuous IV infusion (at 1.0 mg/kg/hr for 5 total hours), there was reportedly increased susceptibility to hypotension and bradycardia in a cardiac arrest model. 72 This discrepancy could be explained by the latter study using much higher doses of DHC due to utilization of a continuous infusion method.…”

A novel caffeoyl triterpene attenuates cerebral ischemic injury with potent anti‐inflammatory and hypothermic effects

“…TRPV1 plays a thermoregulatory role and expresses mainly on a subset of sensory neurons in the peripheral and central nervous system, and TRPV1 activation might induce hypothermia (Gavva 2008) and ameliorate the injuries induced by ischemic insult (Khatibi et al 2011;Muzzi et al 2012;Cao et al 2014). Interestingly, our preliminary in vivo experiment observed that the reduction in the infarct area resulting from B-CA treatment was nearly reversed when the hypothermic effect was effectively inhibited by TRPV1 antagonist AMG517 (data not shown).…”

Dihydrocapsaicin-induced hypothermia after asphyxiai cardiac arrest in rats

“…Several candidates targeting distinct signaling pathways have been tested for PIH including a neurotensin receptor agonist HPI201/ABS201 in stroke and TBI models [3, 4], a cannabinoid receptor agonist WIN55, 212-2 in a ventricular defibrillation CA model [5], the A1 adenosine receptor agonist 8-SPT in an asphyxial-CA model [6], the muscarinic cholinergic partial agonist U-80816E in the gerbil brief bilateral carotid occlusion ischemia model [7], a dopaminergic agonist Talipexole in stroke model [8], a serotonergic agonist S14671 in a stroke model [9] and the transient receptor potential cation channel vanilloid type 1 (TRPV1) agonist dihydrocapsaicin (DHC) in a stroke model [10]. …”

“…DHC, a capsaicin analog, is roughly 65% more effective than capsaicin in producing hypothermia [12], and is consequently a promising candidate for PIH. The capability of DHC to lower body temperature has been validated in healthy mice, rats, cows and monkeys [13, 14] and in stroke mice [10]. However, DHC has displayed cardiovascular effects [15], and whether CA victims could tolerate DHC has not been determined.…”