Exercise and Nutraceuticals: Eminent Approach for Diabetic Neuropathy.

Diabetic neuropathy is an incapacitating chronic pathological condition that encompasses a large group of diseases and manifestations of nerve damage. It affects approximately 50% of patients with diabetes mellitus. Autonomic, sensory, and motor neurons are affected. Disabilities are severe, along with poor recovery and diverse pathophysiology. Physical exercise and herbal- based therapies have the potential to decrease the disabilities associated with diabetic neuropathy. Aerobic exercises like walking, weight lifting, the use of nutraceuticals and herbal extracts are found to be effective. Literature from the public domain was studied emphasizing various beneficial effects of different exercises, herbal and nutraceuticals for their therapeutic action in diabetic neuropathy. Routine exercises and administration of herbal and nutraceuticals, either the extract of plant material containing the active phytoconstituent or isolated phytoconstituent at safe concentration, have been shown to have promising positive action in the treatment of diabetic neuropathy. Exercise has shown promising effects on vascular and neuronal health. It has proven to be well effective in the treatment as well as prevention of diabetic neuropathy by various novel mechanisms, including Herbal and nutraceuticals therapy. They primarily show the anti-oxidant effect, secretagogue, anti-inflammatory, analgesic, and neuroprotective action. Severe adverse events are rare with these therapies. The current review investigates the benefits of exercise and nutraceutical therapies in the treatment of diabetic neuropathy.

Neuroprotective offerings by agmatine.

Agmatine, an endogenous polyamine in CNS, is derived from arginine by dearboxylation. Like polyamines, agmatine has been studied for its neuroprotetive effects. At present, a large body of experimental evidences has been gathered that demonstrate the neuroprotective effects of agmatine. The neuroprotective effects have been observed in various CNS cell lines and animal models against the excitotocity, oxidative damage, corticosteroidid induced neurotoxicity, ischemic/hypoxic or oxygen-glucose deprivation toxicity, spinal cord injury and traumatic brain injury. The studies have been extended to rescue of retinal ganglion cells from toxicities. The mechanistic studies suggest that neuroprotection offered by agmatine can be assigned to its multimolecular biological effects. These include its action as glutamatergic receptor antagonist, α2-adrenoceptor agonist, imidazoline binding site ligand, NOS inhibitor, ADP ribosylation inhibitor, and blocker of ATP-sensitive potassium and voltage-gated calcium channels, anti-apoptotic and antioxidant. Its action as regulator for polyamine synthesis, insulin release assists the neuroprotection. The cumulative evidences of preclinical studies support the possible use of agmatine as an agent for neuronal damage and neurodegenerative diseases. However, it will be hasty to assert and promote agmatine as a novel therapeutic agent for neuroprotection. The review is focused on the role of agmatine in different types and mechanisms of neural injuries. The aspects of concern like dose range, pharmacokinetics of exogenous agmatine, levels of endogenous agmatine during events of injury etc. has to be addressed.

Acute orexigenic effect of agmatine involves interaction between central α2-adrenergic and GABAergic receptors.

Agmatine and GABA have been abundantly expressed in brain nuclei involved in regulation of energy homeostasis and promoting stimulation of food intake in rodents. However, their mutual interaction, if any, in the elicitation of feeding behavior is largely remains unclear. The current study provides experimental evidence for the possible interaction of agmatine, adrenergic and GABAergic systems in stimulation of feeding in satiated rats. Satiated rats fitted with intracerebroventricular (i.c.v.) cannulae and were administered agmatine, alone or jointly with (a) GABAA receptor agonist, muscimol, diazepam or antagonist bicuculline and flumazenil, GABAA positive modulator, allopregnanolone or negative modulator of GABAA receptor, dehydroepiandrosterone (b) In view of the high affinity of agmatine for α2-adrenoceptors and the close association between α2-adrenoceptors and GABAergic system, the effect of their modulators on feeding elicited by agmatine/GABAergic agonists were also examined. I.c.v. administration of agmatine (40-80µg/rat) induces the significant orexigenic effect in satiated rats. The orexigenic effect of agmatine was potentiated by muscimol (25ng/rat, i.c.v.); diazepam (0.5mg/kg, i.p.); allopregnanolone (0.5mg/kg, s.c.) and blocked by bicuculline (1mg/kg, i.p.) and dehydroepiandrosterone (4mg/kg,s.c.). However, it remained unaffected in presence of flumazenil (25ng/rat, i.c.v.). The orexigenic effect of agmatine and GABAergic agonists was potentiated by a α2-adrenoceptors agonist, clonidine (10ng/rat, i.c.v.) and blocked by its antagonist, yohimbine (5µg/rat, i.c.v.). Yohimbine also blocked the hyperphagic effect elicited by ineffective dose combination of agmatine (5µg/rat, i.c.v.) with muscimol (25ng/rat, i.c.v.) or diazepam (0.5mg/kg, i.p.) or allopregnanolone (0.5mg/kg,s.c.). The results of the present study suggest that agmatine induced α2-adrenoceptors activation might facilitate GABAergic activity to stimulate food intake in satiated rats.

Participation of central imidazoline binding sites in antinociceptive effect of ethanol and nicotine in rats.

Despite synergistic morbidity and mortality, concomitant consumption of alcohol and tobacco is increasing, and their antinociceptive effect has been linked with co-abuse. Present study was designed to investigate the role of imidazoline binding sites in the antinociceptive effect of nicotine, ethanol, and their combination. Separate group of male Sprague-Dawley rats (200-250 g) were treated with different doses of alcohol (0.50-2 g/kg, i.p.) or nicotine (0.25-1 mg/kg, i.p.), and their combination evaluated in tail flick test. Influence of endogenous imidazoline binding site ligands, agonist, and antagonists were determined by their prior treatment with effective or subeffective doses of either ethanol or nicotine. Ethanol, nicotine, or their subeffective dose combination exhibited significant antinociceptive effects in dose-dependent manner. Antinociceptive effect of ethanol and nicotine was significantly augmented by intracerebroventricular (i.c.v.) administration of endogenous imidazoline receptor ligands, harmane (25 µg/rat, i.c.v.) and agmatine (10 µg/rat, i.c.v.), as well as imidazoline I1 /α2 adrenergic receptor agonist, clonidine (2 µg/rat, i.c.v.), I1 agonist moxonidine (25 µg/rat, i.c.v.), and imidazoline I2 agonist, 2-BFI (10 µg/rat, i.c.v.). Conversely, antinociception elicited by ethanol or nicotine or their subeffective dose combination was antagonized by pretreatment with imidazoline I1 antagonist, efaroxan (10 µg/rat, i.c.v.), and I2 antagonist, idazoxan (4 µg/rat, i.c.v.), at their per se ineffective doses. These findings project imidazoline binding ligands as important therapeutic molecules for central antinociceptive activity as well as may reduce the co-abuse potential of alcohol and nicotine.

Repeated agmatine treatment attenuates nicotine sensitization in mice: modulation by alpha2-adrenoceptors.

Agmatine [2-(4-aminobutyl)guanidine] is an endogenous amine proposed as a neurotransmitter/neuromodulator that binds to multiple target receptors in brain. Besides, many central and peripheral functions, agmatine have been implicated in the process of drug addiction. The purpose of the present study was to examine the effects of centrally injected agmatine on nicotine induced locomotor sensitization in Swiss male mice. Our data shows that repeated injections of nicotine (0.4 mg/kg, sc, twice daily for 7 days) gradually increased locomotion during 7 days development period or after 3 days (nicotine) withdrawal phase challenged with nicotine (0.4 mg/kg, sc) on day 11. Mice were pretreated with agmatine (40-80 microg, icv) or agents known to increase endogenous brain agmatine levels [e.g. an agmatine biosynthetic precursor, L-arginine (80 microg, icv), ornithine decarboxylase inhibitor, difluoromethyl-ornithine (50 microg, icv), diamine oxidase inhibitor, aminoguanidine (25 microg, icv) and agmatinase inhibitor, arcaine (50 microg, icv)] 30 min before daily first nicotine injection or during nicotine withdrawal phase. All these treatments attenuated the development as well as incubation of locomotor sensitization to nicotine. Coadministration of agmatine (20 microg, icv) and alpha(2)-adrenoreceptors agonist, clonidine (0.1 microg, icv) evoked synergistic inhibition of nicotine sensitization. Conversely, prior administration of alpha(2)-adrenoceptor antagonist, yohimbine (5mg/kg, ip) or idazoxan (0.4 mg/kg, ip) reversed the inhibitory effect of agmatine on nicotine sensitization. There was no significant difference in activity between mice injected with any of these agents/saline alone and saline/saline groups. These data indicate that agmatine attenuates nicotine induced locomotor sensitization via a mechanism which may involve alpha(2)-adrenergic receptors. Thus, agmatine might have therapeutic implications in the treatment of nicotine addiction and deserve further investigations.