Effect of high-fat diet on cerebral pathological changes of cerebral small vessel disease in SHR/SP rats.

Cerebral small vessel diseases (CSVD) are neurological disorders associated with microvessels, manifested pathologically as white matter (WM) changes and cortical microbleeds, with hypertension as a risk factor. Additionally, a high-fat diet (HFD) can affect peripheral vessel health. Our study explored how HFD affects cerebral small vessels in normotensive WKY, hypertensive SHR, and SHR/SP rats. The MRI results revealed that HFD specifically increased WM hyperintensity in SHR/SP rats. Pathologically, it increased WM pallor and vacuolation in SHR and SHR/SP rats. Levels of blood-brain barrier (BBB) protein claudin 5 were decreased in SHR and SHR/SP compared to WKY, with HFD having minimal impact on these levels. Conversely, collagen IV levels remained consistent among the rat strains, which were increased by HFD. Consequently, HFD caused vessel leakage in all rat strains, particularly within the corpus callosum of SHR/SP rats. To understand the underlying mechanisms, we assessed the levels of hypoxia-inducible factor-1α (HIF-1α), Gp91-phox, and neuroinflammatory markers astrocytes, and microglia were increased in SHR and SHR/SP compared to WKY and were further elevated by HFD in all rat strains. Gp91-phox was also increased in SHR and SHR/SP compared to WKY, with HFD causing an increase in WKY but little effect in SHR and SHR/SP. In conclusion, our study demonstrates that HFD, in combined with hypertension, intensifies cerebral pathological alterations in CSVD rats. This exacerbation involves increased oxidative stress and HIF-1α in cerebral vessels, triggering neuroinflammation, vascular basement membrane remodeling, IgG leakage, and ultimately WM damage.

Multiple actions of extracellular ATP and adenosine on calcium currents mediated by various purinoceptors in neurons of nucleus tractus solitarius.

Whole-cell patch-clamp recordings were performed on freshly dissociated nucleus tractus solitarius (NTS) of rat to determine the action of extracellular adenosine 5'-triphosphate (ATP) and adenosine (ADO) on voltage-dependent calcium channel (VDCC) currents (I(Ca)). Application of ATP and ATP-analog inhibited I(Ca). The rank order of potency of inhibition of I(Ca) was 2-methylthioATP (2-MeSATP) > ATP > adenosine 5'-diphosphate (ADP) >> alpha,beta-methylene ATP (alpha,beta-MeATP) = uridine 5'-triphosphate (UTP). Application of ADO receptor agonists also inhibited I(Ca). The rank order of potency of inhibition of I(Ca) was N(6)-cyclohexyladenosine (CHA) > ADO > 2-(4-(2-carboxyethyl)phenylethylamino)adenosine-5'-N-ethylcarboxamideadenosine (CGS-21680) > N(6)-2-(4-aminophenyl)ethyladenosine (APNEA). Application of prepulse attenuated these inhibition. Both intracellular dialysis of guanosin 5'-O-(2-thiodiphosphate) (GDP-beta-S) and anti-G(i) antibody also attenuated these inhibition. L-, N- and P/Q-type VDCCs were inhibited by ATP. In contrast, N- and P/Q-type VDCCs were inhibited by ADO. In addition to inhibition, application of 100 microM ATP facilitated I(Ca). Intracellular dialysis of GDP-beta-S did not attenuate these facilitations. In conclusion, activation of P2Y purinoceptors inhibits L-, N- and P/Q-types VDCCs via G(i)-protein betagamma subunits. Activation of A(1) and/or A(2) receptors inhibit N- and P/Q-types VDCCs via G(i)-protein betagamma subunits. Activation of P2X purinoceptors facilitates Ca(2+) entry in NTS.

The effects of cilostazol on nerve conduction velocity and blood flow: acute and chronic cauda equina compression in a canine model.

STUDY DESIGN: Analyses of improvements in nerve conduction velocity (NCV) and blood flow after administering cilostazol in a dog model of experimental acute and chronic cauda equina compression. OBJECTIVE: To determine whether cilostazol improves NCV and blood flow, and cilostazol inhibits blood clots in capillaries of nerve roots after cauda equina compression. SUMMARY AND BACKGROUND DATA: Reduction in blood flow is an important factor in neurogenic intermittent claudication for lumbar spinal stenosis. Prostaglandin E1 (PGE1) and calcitonin have been reported to improve blood flow and neurogenic intermittent claudication in clinical and experimental studies. Cilostazol affects vasodilator and antiplatelet activity, and protects endothelial cells in blood vessels. METHODS: Experimental groups in the acute compression study (n = 40) were divided into 4 treatment groups. Low-dose (3 microg/kg/min), medium-dose (10 microg/kg/min), or high-dose (30 microg/kg/min) cilostazol or a control vehicle were administered intravenously after cauda equina compression. NCV and blood flow were measured during the observation period (n = 20 measurements for each). Another 12 animals were used to evaluate chronic compression. Cilostazol was administered for 6 days orally 1 day after compression treatment group (n = 6); the nontreatment group (n = 6) did not receive any drug. NCV was measured immediately after and 7 days after compression. Blood flow was measured 7 days after compression. RESULTS: In the acute compression study, NCV in the medium-dose group was significantly higher than that in the other groups during the compression period (P < 0.05). During the recovery period, there was no significant difference in NCV among groups. In the chronic compression study, NCV and blood flow in the cilostazol group were significantly higher than those in the control group (P < 0.05). CONCLUSION: Cilostazol improved NCV and blood flow to the cauda equina in this dog model. Cilostazol might be a potential agent to improve symptoms due to compression of cauda equina and/or cauda equina dysfunction.

Pathomechanisms of nerve root injury caused by disc herniation: an experimental study of mechanical compression and chemical irritation.

STUDY DESIGN: An electrophysiologic and histologic study on nerve roots after mechanical compression and/or local application of nucleus pulposus (NP) was performed. OBJECTIVE: To assess the effects of mechanical compression and/or chemical irritation caused by NP. SUMMARY OF BACKGROUND DATA: It has been shown that application of NP to nerve roots without compression induces histologic and functional changes in nerve roots and the dorsal root ganglia. In clinical situations, however, mechanical compression has also been considered an important factor in disc herniation. METHODS: Eighteen dogs (9-15 kg) were used in this study. Four groups were used to assess the effect of each factor: 1) sham group (n = 3); 2) NP group (NP applied under the S1 lamina) (n = 5); 3) comp group (a plastic balloon placed under the S1 lamina) (n = 5); and 4) comp+NP group (a balloon and NP placed under the S1 lamina) (n = 5). Ascending cauda equina action potentials (CEAPs) and cauda equina-sensory nerve conduction velocity (SCV) were recorded before, immediately after, and 1 week after treatment. Histologic changes were also assessed by light microscopy. RESULTS: There were no significant differences in CEAP and SCV among the four groups immediately after the treatment. However, 1 week after treatment, the amplitudes in the NP group, comp group, and comp+NP group were statistically significantly lower compared with those in the sham group. The comp+NP group showed significantly lower amplitude than did the NP group and comp group. Immediately after treatment, SCV in the NP group and comp group did not show significant differences compared with that in the sham group. However, 1 week after treatment, SCV in the comp+NP group was significantly lower compared with that in the sham group. Histologic changes such as intraneural edema, Schwann cell edema, and nerve fiber injury seemed to be more pronounced in the comp+NP group than in the other groups. CONCLUSIONS: It was shown that each of the assessed factors induces nerve dysfunction. However, the combination of mechanical compression (mass effect of herniated NP) and chemical irritation (inflammation around nerve root) may induce more nerve root injury than each factor per se.

Local application of disc-related cytokines on spinal nerve roots.

STUDY DESIGN: To analyze the effects of tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma on cauda equina function and to define if any of these cytokines could induce nerve root dysfunction comparable with the situation with application of nucleus pulposus. SUMMARY OF BACKGROUND DATA: Proinflammatory cytokines derived from the intervertebral disc have been suggested to mediate the nucleus pulposus-induced nerve root injury following local application of nucleus pulposus. However, it is not known if such cytokines may induce similar injury if applied separately. METHODS: A total of 29 pigs were used. Nucleus pulposus was harvested from lumbar discs and applied to the sacrococcygeal cauda equina following laminectomy of the first coccygeal vertebra in seven pigs. Five pigs received 1.66 microg of tumor necrosis factor-alpha, five pigs received 0.85 microg of interleukin-1beta, and five pigs received 1.66 microg of interferon-gamma. Seven pigs received autologous fat for control. Nerve conduction velocity was studied by local electrical stimulation and recordings in the tail muscles 7 days after the application. RESULTS: Application of nucleus pulposus and fat induced similar effects as seen in previous studies, with normal nerve conduction velocity for fat and a significant reduction for nucleus pulposus. Application of both interleukin-1beta and IFN-gamma induced slight reductions of nerve conduction velocity compared with fat, but they were not statistically significant. Tumor necrosis factor-alpha, however, induced a reduction of the velocity that was even more pronounced than for nucleus pulposus. CONCLUSION: Based on previous observations and the data of the present study, one may conclude that tumor necrosis factor-alpha from nucleus pulposus cells seems to be intimately involved with the basic pathophysiologic events leading to both nerve root dysfunction and pain after local, epidural application of nucleus pulposus. One may therefore also suspect that pharmacologic inhibition of tumor necrosis factor-alpha may at least theoretically be considered in the clinical situation with disc herniation and sciatica.